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.

Correction to: Neurologically asymptomatic cerebral oligometastatic prostate carcinoma metastasis identified on [Ga]Ga-THP-PSMA PET/CT.

An amendment to this paper has been published and can be accessed via the original article.

Neurologically asymptomatic cerebral oligometastatic prostate carcinoma metastasis identified on [Ga]Ga-THP-PSMA PET/CT.

BACKGROUND: Brain metastases from prostate cancer are rare and usually only occur in the context of widespread systemic disease. This is the first case report of a solitary brain oligometastasis, in a neurologically intact prostate cancer patient with no other systemic disease, detected using [68Ga]Ga-THP-PSMA PET/CT and only the second one using a PSMA-based radiopharmaceutical. CASE PRESENTATION: We report the case of a prostate cancer patient presenting 5 years after robot-assisted laparoscopic prostatectomy with biochemical recurrence, no neurological symptoms, and in the absence of metastatic lesions in the body on conventional imaging. A solitary cerebral metastasis was detected using [68Ga]Ga-THP-PSMA PET/CT, surgically resected, leading to a drop in serum PSA and a good recovery. CONCLUSION: In this case, [68Ga]Ga-THP-PSMA PET/CT resulted in a major change in clinical management and avoided additional morbidity associated with delayed diagnosis and treatment. This report demonstrates the importance of considering the presence of metastatic disease outside the conventional locations of prostate cancer spread, as well as the importance of ensuring comprehensive [68Ga]Ga-PSMA PET/CT coverage from vertex to upper thighs.

Added value of diffusion-weighted MRI for nodal radiotherapy planning in pelvic malignancies.

PURPOSE: To evaluate the added value of diffusion-weighted imaging (DWI) to T2-weighted imaging (T2WI) for improved identification of pelvic lymph nodes (LN) by radiation oncologists. METHODS/PATIENTS: This retrospective study included 20 patients with histopathologically proven node-negative prostate cancer. All patients underwent 3T-MRI of the prostate; matched axial T2WI and DWI sequences were assessed by an experienced uro-radiologist as the reference standard. Consultant and specialist registrar radiation oncologists were asked to identify all LN first on T2WI alone (read 1) and then on T2WI and DWI combined (read 2); LN were measured in size and divided into true positives (TP), false positives (FP) and false negatives (FN). Sensitivity, positive predictive value (PPV) and false negative rate (FNR) were then calculated and compared using Pearson's Chi square test. RESULTS: A total of 177 LN comprised the reference standard. 16 TP, 16 FP and 161 FN LN (sensitivity 9.0%, PPV 50.0%, FNR 91.0%) and 124, 15 and 53 LN (70.1%, 89.2%, 30%) were identified by reader 1 on reads 1 and 2, respectively; χ2 (2, N = 385) = 137.8, p < 0.0001. 27, 21 and 150 LN (15.3%, 56.3%, 84.8%) and 120, 13 and 57 LN (67.8%, 90.2%, 32.2%) were identified by reader 2 on the two reads; χ2 (2, N = 388) = 102.4, p < 0.0001. CONCLUSIONS: Adding DWI to T2WI significantly improved identification of pelvic LN by radiation oncologists and can therefore be regarded as a useful LN contouring technique for RT planning in pelvic malignancies.

The value of image-guided intensity-modulated radiotherapy in challenging clinical settings.

OBJECTIVE: To illustrate the wider potential scope of image-guided intensity-modulated radiotherapy (IG-IMRT), outside of the "standard" indications for IMRT. METHODS: Nine challenging clinical cases were selected. All were treated with radical intent, although it was accepted that in several of the cases the probability of cure was low. IMRT alone was not adequate owing to the close proximity of the target to organs at risk, the risk of geographical miss, or the need to tighten planning margins, making image-guided radiotherapy an essential integral part of the treatment. Discrepancies between the initial planning scan and the daily on-treatment megavoltage CT were recorded for each case. The three-dimensional displacement was compared with the margin used to create the planning target volume (PTV). RESULTS: All but one patient achieved local control. Three patients developed metastatic disease but benefited from good local palliation; two have since died. A further patient died of an unrelated condition. Four patients are alive and well. Toxicity was low in all cases. Without daily image guidance, the PTV margin would have been insufficient to ensure complete coverage in 49% of fractions. It was inadequate by >3 mm in 19% of fractions, and by >5 mm in 9%. CONCLUSION: IG-IMRT ensures accurate dose delivery to treat the target and avoid critical structures, acting as daily quality assurance for the delivery of complex IMRT plans. These patients could not have been adequately treated without image guidance. ADVANCES IN KNOWLEDGE: IG-IMRT can offer improved outcomes in less common clinical situations, where conventional techniques would provide suboptimal treatment.

Consideration of the likely benefit from implementation of prostate image-guided radiotherapy using current margin sizes: a radiobiological analysis.

OBJECTIVE: To estimate the benefit of introduction of image-guided radiotherapy (IGRT) to prostate radiotherapy practice with current clinical target volume-planning target volume (PTV) margins of 5-10 mm. METHODS: Systematic error data collected from 50 patients were used together with a random error of σ=3.0 mm to model non-IGRT treatment. IGRT was modelled with residual errors of Σ=σ=1.5 mm. Population tumour control probability (TCP(pop)) was calculated for two three-dimensional conformal radiotherapy techniques: two-phase and concomitant boost. Treatment volumes and dose prescriptions were ostensibly the same. The relative field sizes of the treatment techniques, distribution of systematic errors and correlations between movement axes were examined. RESULTS: The differences in TCP(pop) between the IGRT and non-IGRT regimes were 0.3% for the two-phase and 1.5% for the concomitant boost techniques. A 2-phase plan, in each phase of which the 95% isodose conformed to its respective PTV, required fields that were 3.5 mm larger than those required for the concomitant boost plan. Despite the larger field sizes, the TCP (without IGRT) in the two-phase plan was only 1.7% higher than the TCP in the concomitant boost plan. The deviation of craniocaudal systematic errors (p=0.02) from a normal distribution, and the correlation of translations in the craniocaudal and anteroposterior directions (p<0.0001) were statistically significant. CONCLUSIONS: The expected population benefit of IGRT for the modelled situation was too small to be detected by a clinical trial of reasonable size, although there was a significant benefit to individual patients. For IGRT to have an observable population benefit, the trial would need to use smaller margins than those used in this study. Concomitant treatment techniques permit smaller fields and tighter conformality than two phases planned separately.

Accelerated BEP: a phase I trial of dose-dense BEP for intermediate and poor prognosis metastatic germ cell tumour.

BACKGROUND: We used bleomycin, etoposide, cisplatin (BEP), the most effective regimen in the treatment of germ cell tumours (GCTs) and increased dose-density by using pegfilgrastim to shorten cycle length. Our aim was to assess safety and tolerability. METHODS: Sixteen male patients with intermediate or poor prognosis metastatic GCT were treated with four cycles of 3-day BEP with G-CSF on a 14-day cycle for a planned relative dose-density of 1.5 compared with standard BEP. RESULTS: Eleven intermediate and five poor prognosis patients were treated. In all, 14 of 16 patients completed the study treatment. Toxicities were comparable to previous studies using standard BEP, except for mucositis and haematological toxicity that were more severe. The overall relative dose-density for all 16 patients was mean 1.38 (range 0.72-1.5; median 1.46). Complete response was achieved after chemotherapy alone in two patients (13%) and following chemotherapy plus surgery in nine additional patients (56%). Four patients (25%) had a partial response and normalised their marker levels. At a median follow-up of 4.4 years (range 2.1-6.8) the estimated 5-year progression-free survival probability is 81% (95% CI 64-100%). CONCLUSION: Accelerated BEP is tolerable without major additional toxicity. A randomised controlled trial will be required to obtain comparative efficacy data.

Practical aspects of implementation of helical tomotherapy for intensity-modulated and image-guided radiotherapy.

AIMS: Image-guided radiotherapy (IGRT) and intensity-modulated radiotherapy (IMRT) represent two important technical developments that will probably improve patient outcome. Helical tomotherapy, provided by the TomoTherapy HiArt system, provides an elegant integrated solution providing both technologies, although others are available. Here we report our experience of clinical implementation of daily online IGRT and IMRT using helical tomotherapy. MATERIALS AND METHODS: Methods were needed to select patients who would probably benefit. Machine-specific commissioning, a quality assurance programme and patient-specific delivery quality assurance were also needed. The planning target volume dose was prescribed as the median dose, with the added criterion that the 95% isodose should cover 99% of the target volume. Although back-up plans, for delivery on conventional linear accelerators, were initially prepared, this practice was abandoned because they were used very rarely. RESULTS: In the first 12 months, 114 patients were accepted for treatment, and 3343 fractions delivered. New starts averaged 2.6 per week, with an average of 17.5 fractions treated per day, and the total number capped at 22. This has subsequently been raised to 24. Of the first 100 patients, 96 were treated with radical intent. Five were considered to have been untreatable on our standard equipment. IGRT is radiographer led and all patients were imaged daily, with positional correction made before treatment, using an action level of 1mm. A formal training programme was developed and implemented before installation. The in-room time fell significantly during the year, reflecting increasing experience and a software upgrade. More recently, after a couch upgrade in April 2009, the mean in-room time fell to 18.6 min. CONCLUSIONS: Successful implementation of tomotherapy was the result of careful planning and effective teamwork. Treatment, including daily image guidance, positional correction and intensity-modulated delivery, is fast and efficient, and can be integrated into routine service. This should encourage the adoption of these technologies.

Practical issues in the implementation of image-guided radiotherapy for the treatment of prostate cancer within a UK department.

AIMS: To study the feasibility of using implanted gold seeds in combination with a commercial software system for daily localisation of the prostate gland during conformal radiotherapy, and to assess the effect this may have on departmental workload. MATERIALS AND METHODS: Six patients had three gold radio-opaque seeds implanted into the prostate gland before starting a course of radiotherapy. The seeds were identified on daily portal images and an automated online system provided immediate vector analysis of discrepancies between the planned and actual daily position of the intraprostatic seeds. In total, 138 interfractional displacements were analysed. The workload impact for the department was assessed using the basic treatment equivalence model, by comparing measurements of daily treatment session durations with a control group of patients receiving standard conformal radiotherapy, matched for treatment complexity. RESULTS: No acute complications of seed insertion were observed. A number of developmental issues required solutions to be identified before clinical implementation was possible. The standard deviations of the set-up and organ motion systematic errors in the left-right, superior-inferior and anterior-posterior directions were 2.4, 3.0 and 2.5 mm, respectively. The standard deviations of the set-up and organ motion random errors calculated were 2.5, 2.9 and 3.7 mm. The mean treatment session duration with this daily prostate localisation system was increased by 3 min compared with matched controls using standard imaging practice. If all radical prostate patients in our department were to receive image-guided radiotherapy in this way, this would increase machine workload time by 2.2 h/day. CONCLUSIONS: The implementation of this image-guided system is feasible. No additional linear accelerator modification is required and standard imaging devices can be used. It would be a useful addition to any department's image-guided radiotherapy developmental strategy.

Reaction of sorbic acid in wheat flour doughs: reaction with thiols.

The general characteristics of the reaction between sorbic acid and thiols are reviewed. Cysteine adds to the conjugated diene in position 5 to form the substituted 3-hexenoic acid. This is labile in acid solution, yielding a quantitative amount of sorbic acid. When wheat flour doughs are treated with sorbic acid and heated, a significant amount of the sorbic acid is not recovered on extraction with methanol. The use of acidified methanol leads to a quantitative recovery of the preservation and evidence is presented to suggest that sorbic acid-thiol adducts are formed. This is the first report of 'reversibly bound' sorbic acid in a food.