Adaptive radiotherapy for bladder cancer – a systematic review

Radiotherapy has been offered as a multi-modality treatment for bladder cancer patients. Due to the significant variation of bladder volume observed throughout the course of treatment, large margins in the range of 20 – 30 mm have been used, unnecessarily irradiating a large volume of normal tissue. With the capability of visualizing soft tissue in Cone Beam Computerized Tomography, there is opportunity to modify or to adapt the plan based on the variation observed during the course of treatment for quality improvement. A literature search was conducted in May 2016, with the aim of examining the adaptive strategies that have been developed for bladder cancer and assessing the efficacy in improving treatment quality. Among the 18 identified publications, three adaptive strategies were reported: Plan of the Day, patient-specific planning target volume and daily reoptimization. Overall, any of the adaptive strategies achieved a significant improvement in reducing the irradiated volume compared to the non-adaptive approach, outweighing the additional resource required for its execution. The amount and the type of resource required vary from strategy to strategy, suggesting the need for the individual institution to assess feasibility based on the existing infrastructure in order to identify the most appropriate strategy for implementation

Comparison of 3 image-guided adaptive strategies for bladder locoregional radiotherapy

The objective of this study was to compare the dosimetric differences of a population-based planning target volume (PTV) approach and 3 proposed adaptive strategies: plan of the day (POD), patient-specific PTV (PS-PTV), and daily reoptimization (ReOpt). Bladder patients (n = 10) were planned and treated to 46 Gy in 23 fractions with a full bladder in supine position by the standard strategy using a population-based PTV. For each patient, the adaptive strategy was executed retrospectively as follows: (1) POD—multiple distributions of various PTV sizes were generated, and the appropriate distribution based on the bladder of the day was selected for each fraction; (2) PS-PTV—population-based PTV was used for the first 5 fractions and a new PTV derived using information from these fractions was used to deliver the remaining 18 fractions; and (3) ReOpt—distribution was reoptimized for each fraction based on the bladder of the day. Daily dose was computed on all cone beam computed tomographies (CBCTs) and deformed back to the planning computed tomography (CT) for dose summation afterward. V95_Accu, the volume receiving an accumulated delivered dose of 43.7 Gy (95% prescription dose), was measured for comparison. Mean V95_Accu (cm3) values were 1410 (standard deviation [SD]: 227), 1212 (SD: 186), 1236 (SD: 199), and 1101 (SD: 180) for standard, POD, PS-PTV, and ReOpt, respectively. All adaptive strategies significantly reduced the irradiated volume, with ReOpt demonstrating the greatest reduction compared with the standard (− 25%), followed by PS-PTV (− 16%) and POD (− 12%). The difference in the magnitude of reduction between ReOpt and the other 2 strategies reached statistical significance (p = 0.0006). ReOpt is the best adaptive strategy at reducing the irradiated volume because of its frequent adaptation based on the daily geometry of the bladder. The need to adapt only once renders PS-PTV to be the best alternative adaptive strategy

Relationship between the magnitude of intraocular pressure during an episode of acute elevation and retinal damage four weeks later in rats

PURPOSE: To determine relationship between the magnitude of intraocular pressure (IOP) during a fixed-duration episode of acute elevation and the loss of retinal function and structure 4 weeks later in rats. METHODS: Unilateral elevation of IOP (105 minutes) was achieved manometrically in adult Brown Norway rats (9 groups; n = 4 to 8 each, 10-100 mm Hg and sham control). Full-field ERGs were recorded simultaneously from treated and control eyes 4 weeks after IOP elevation. Scotopic ERG stimuli were white flashes (-6.04 to 2.72 log cd.s.m(-2)). Photopic ERGs were recorded (1.22 to 2.72 log cd.s.m(-2)) after 15 min of light adaptation (150 cd/m(2)). Relative amplitude (treated/control, %) of ERG components versus IOP was described with a cummulative normal function. Retinal ganglion cell (RGC) layer density was determined post mortem by histology. RESULTS: All ERG components failed to recover completely normal amplitudes by 4 weeks after the insult if IOP was 70 mmHg or greater during the episode. There was no ERG recovery at all if IOP was 100 mmHg. Outer retinal (photoreceptor) function demonstrated the least sensitivity to prior acute IOP elevation. ERG components reflecting inner retinal function were correlated with post mortem RGC layer density. CONCLUSIONS: Retinal function recovers after IOP normalization, such that it requires a level of acute IOP elevation approximately 10 mmHg higher to cause a pattern of permanent dysfunction similar to that observed during the acute event. There is a 'threshold' for permanent retinal functional loss in the rat at an IOP between 60 and 70 mmHg if sustained for 105 minutes or more

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Improving precision of radiotherapy for prostate and bladder cancer

Aims: The aim of this thesis is to demonstrate how the use of volumetric images could improve the precision of bladder and prostate radiotherapy.Methods: A series of studies, including seven in silico analyses, one prospective study, and two systematic reviews, were conducted in collaboration with a multidisciplinary team on using volumetric images to improve the precision of bladder and prostate radiotherapy. The findings from these studies were presented in the ten peer-reviewed publications included in this thesis. Each publication was critically evaluated and categorized under the following themes: 1) Tracking the target; 2) Adapting to the target and Organs at Risk (OARs) and 3) Estimating the delivered dose to the target and OARs.Results: The ability to track the target using volumetric images facilitates the generation of a patient specific treatment volume for bladder radiotherapy to reduce irradiation of OARs (Publication 1 and 2). Its clinical adoption was supported by evidence generated from various quality assurance studies (Publication 3-5). Findings on the various aspects of the adaptation workflow for bladder radiotherapy were categorized using the R-IDEAL framework to recognize the amount of evidence available to demonstrate its technical feasibility and efficacy and the need for more clinical studies for validation (Publication 6). Adaptation for prostate was compared against tracking, enabling the identification of factors affecting the effectiveness of adaptation (Publication 7). The delivered dose estimation workflow was developed based on information synthesized from a literature review (Publication 8) and was applied in pre-clinical and quality improvement studies to demonstrate the feasibility of alternative intervention in clinical studies and support changes in clinical practice (Publication 9-10).Conclusion: The publications presented in this thesis have shown how I have significantly contributed to the knowledge of using volumetric images to improve the precision of bladder and prostate radiotherapy through tracking, adaptation and estimation of delivered dose.</p

Failure mechanisms of a spudcan penetrating next to an existing footprint

Reinstallation of mobile jack-up rigs next to existing footprints is a problematic operation because the spudcan located near the footprints is subjected to eccentric and/or inclined loading conditions. Geotechnical centrifuge studies have measured these loads for combinations of changing footprint geometry, footprint soil properties and the offset of the reinstallation from the footprint centre. These tests have been of full model spudcans in order to accurately measure the combined loads developed. They have not provided information on the mechanisms of failure occurring during this complex installation. Observations from a visualisation test, where a half spudcan is penetrated against a transparent window in a geotechnical centrifuge, are reported in this paper. The mechanisms of failure at different stages during the penetration are presented

The Effect of dose grid resolution on dose volume histograms for slender organs at risk during pelvic intensity-modulated radiotherapy

Purpose: There are enduring uncertainties regarding the optimal dose grid resolution for use with pelvic intensity-modulated radiotherapy (IMRT) plans in which the adjacent organs at risk are slender and transect the field edge. Therefore, this study evaluated the effect of dose grid resolution on bladder wall dose-volume histogram (DVH) calculations for prostate IMRT plans. Materials and Methods: The planning computed tomography scans and clinical plans from 15 prostate cancer patients were included in this analysis. For each study computed tomography, the entire inner and outer bladder surfaces were delineated. Nine versions of the clinical plan were created, varying interval between the dose grid calculation points uniformly in three dimensions, whereas all other plan parameters were kept constant. The dose grid increments tested were 1-10 mm. The plans were recalculated and the bladder wall DVH compared against the study benchmark (1 mm grid). Results: All the dose grid increments evaluated resulted in a systematic overestimation of the bladder wall volume receiving low doses and an underestimation of the volume receiving high doses. Grid increments 5.0 mm resulted in mean volume differences greater than 2 cm³. Individual patient analysis revealed that only the 1.5 mm increment resulted in maximum volume differences ≤1 cm³ for every patient across the full length of the DVH curve. Bladder wall thickness ranged from 1.7 to 4.4mm and displayed no correlation with the magnitude of the dose grid effect. Conclusions: For an accurate DVH calculation for bladder wall during IMRT planning for prostate cancer, a 1.5 mm dose grid increment is recommended. This finding was unaffected by a normal range in bladder wall thickness. It is suggested that the application of any new treatment planning technique or organ delineation method be accompanied with an evaluation of optimal dose grid resolution.6 page(s