Acute Toxicity of Hypofractionated and Conventionally Fractionated (Chemo)Radiotherapy Regimens for Bladder Cancer: An Exploratory Analysis from the RAIDER Trial.

AIMS: Adding concurrent (chemo)therapy to radiotherapy improves outcomes for muscle-invasive bladder cancer patients. A recent meta-analysis showed superior invasive locoregional disease control for a hypofractionated 55 Gy in 20 fractions schedule compared with 64 Gy in 32 fractions. In the RAIDER clinical trial, patients undergoing 20 or 32 fractions of radical radiotherapy were randomised (1:1:2) to standard radiotherapy or to standard-dose or escalated-dose adaptive radiotherapy. Neoadjuvant chemotherapy and concomitant therapy were permitted. We report exploratory analyses of acute toxicity by concomitant therapy-fractionation schedule combination. MATERIALS AND METHODS: Participants had unifocal bladder urothelial carcinoma staged T2-T4a N0 M0. Acute toxicity was assessed (Common Terminology Criteria for Adverse Events) weekly during radiotherapy and at 10 weeks after the start of treatment. Within each fractionation cohort, non-randomised comparisons of the proportion of patients reporting treatment emergent grade 2 or worse genitourinary, gastrointestinal or other adverse events at any point in the acute period were carried out using Fisher's exact tests. RESULTS: Between September 2015 and April 2020, 345 (163 receiving 20 fractions; 182 receiving 32 fractions) patients were recruited from 46 centres. The median age was 73 years; 49% received neoadjuvant chemotherapy; 71% received concomitant therapy, with 5-fluorouracil/mitomycin C most commonly used: 44/114 (39%) receiving 20 fractions; 94/130 (72%) receiving 32 fractions. The acute grade 2+ gastrointestinal toxicity rate was higher in those receiving concomitant therapy compared with radiotherapy alone in the 20-fraction cohort [54/111 (49%) versus 7/49 (14%), P < 0.001] but not in the 32-fraction cohort (P = 0.355). Grade 2+ gastrointestinal toxicity was highest for gemcitabine, with evidence of significant differences across therapies in the 32-fraction cohort (P = 0.006), with a similar pattern but no significant differences in the 20-fraction cohort (P = 0.099). There was no evidence of differences in grade 2+ genitourinary toxicity between concomitant therapies in either the 20- or 32-fraction cohorts. CONCLUSION: Grade 2+ acute adverse events are common. The toxicity profile varied by type of concomitant therapy; the gastrointestinal toxicity rate seemed to be higher in patients receiving gemcitabine.

Calculating radiotherapy margins based on Bayesian modelling of patient specific random errors.

Collected real-life clinical target volume (CTV) displacement data show that some patients undergoing external beam radiotherapy (EBRT) demonstrate significantly more fraction-to-fraction variability in their displacement ('random error') than others. This contrasts with the common assumption made by historical recipes for margin estimation for EBRT, that the random error is constant across patients. In this work we present statistical models of CTV displacements in which random errors are characterised by an inverse gamma (IG) distribution in order to assess the impact of random error variability on CTV-to-PTV margin widths, for eight real world patient cohorts from four institutions, and for different sites of malignancy. We considered a variety of clinical treatment requirements and penumbral widths. The eight cohorts consisted of a total of 874 patients and 27 391 treatment sessions. Compared to a traditional margin recipe that assumes constant random errors across patients, for a typical 4 mm penumbral width, the IG based margin model mandates that in order to satisfy the common clinical requirement that 90% of patients receive at least 95% of prescribed RT dose to the entire CTV, margins be increased by a median of 10% (range over the eight cohorts -19% to +35%). This substantially reduces the proportion of patients for whom margins are too small to satisfy clinical requirements.

Finding the optimal statistical model to describe target motion during radiotherapy delivery--a Bayesian approach.

Early approaches to characterizing errors in target displacement during a fractionated course of radiotherapy assumed that the underlying fraction-to-fraction variability in target displacement, known as the 'treatment error' or 'random error', could be regarded as constant across patients. More recent approaches have modelled target displacement allowing for differences in random error between patients. However, until recently it has not been feasible to compare the goodness of fit of alternate models of random error rigorously. This is because the large volumes of real patient data necessary to distinguish between alternative models have only very recently become available. This work uses real-world displacement data collected from 365 patients undergoing radical radiotherapy for prostate cancer to compare five candidate models for target displacement. The simplest model assumes constant random errors across patients, while other models allow for random errors that vary according to one of several candidate distributions. Bayesian statistics and Markov Chain Monte Carlo simulation of the model parameters are used to compare model goodness of fit. We conclude that modelling the random error as inverse gamma distributed provides a clearly superior fit over all alternatives considered. This finding can facilitate more accurate margin recipes and correction strategies.

Palliative radiation therapy for localized prostate symptoms in hormone refractory prostate cancer.

Hormone refractory prostate cancer (HRPCa) can cause debilitating local pelvic symptoms including urinary obstruction, pelvic pain, haematuria and obstructive rectal symptoms. High-dose palliative radiation therapy (RT) is used in many centres to relieve these symptoms despite limited published evidence for its efficacy. This study aimed to assess if RT provides effective and durable palliation for local prostate symptoms in HRPCa. Thirty-five HRPCa patients received RT to the prostate for local symptoms between November 2002 and March 2006. The median dose was 60 Gy in 30 fractions (range 30-70 Gy). Response around a 6-month time point was scored as complete resolution, partial resolution, no change or local progression. Time to progression (defined as new or recurrent symptoms) or persistence of symptoms was recorded. Factors influencing outcome, such as dose, type and number of symptoms and previous transurethral resection, were examined. Twenty-one (60%) patients had a complete (n=3) or partial improvement (n=18) in symptoms. All three complete responders had haematuria as their only symptom. In the eight (23%) patients with local progression, half progressed during treatment and all had done so within 3 months. This series represents a bigger cohort than any reported in published works examining this issue. It suggests that radiation is effective in palliating the local pelvic symptoms in HRPCa.

Determination of morphine, oripavine and pseudomorphine using capillary electrophoresis with acidic potassium permanganate chemiluminescence detection.

A simple and robust capillary electrophoresis chemiluminescence detection system for the determination of morphine, oripavine and pseudomorphine is described, based upon the reaction of these analytes with acidic potassium permanganate in the presence of sodium polyphosphate. The reagent solution was contained in a quartz detection cell which also held both the capillary and the anode. The resultant chemiluminescence was monitored directly using a photomultiplier tube mounted flush against the base of the detection cell. To ensure that no migration of the permanganate anion occurred, the anode was placed at the detector end whilst the electroosmotic flow was reversed by the addition of hexadimethrine bromide (0.001% m/v) to the electrolyte. The three analytes were separated counter to the electroosmotic flow via their interaction with alpha-cyclodextrin. The methodology realised detection limits (3 x S/N) of 2.5 x 10(-7) M for both morphine and oripavine and 5 x 10(-7) M for pseudomorphine. The relative standard deviations of the migration times and the peak heights for the three analytes ranged from 0.6 up to 0.8% and from 1.5 up to 2.1%, respectively.