Types of Publications
Journal articles
PURPOSE: To examine patterns of bladder wall motion during high-dose hypofractionated bladder radiotherapy and to validate a novel adaptive planning method, A-POLO, to prevent subsequent geographic miss. METHODS AND MATERIALS: Patterns of individual bladder filling were obtained with repeat computed tomography planning scans at 0, 15, and 30minutes after voiding. A series of patient-specific plans corresponding to these time-displacement points was created. Pretreatment cone-beam computed tomography was performed before each fraction and assessed retrospectively for adaptive intervention. In fractions that would have required intervention, the most appropriate plan was chosen from the patient's "library," and the resulting target coverage was reassessed with repeat cone-beam computed tomography. RESULTS: A large variation in patterns of bladder filling and interfraction displacement was seen. During radiotherapy, predominant translations occurred cranially (maximum 2.5 cm) and anteriorly (maximum 1.75 cm). No apparent explanation was found for this variation using pretreatment patient factors. A need for adaptive planning was demonstrated by 51% of fractions, and 73% of fractions would have been delivered correctly using A-POLO. The adaptive strategy improved target coverage and was able to account for intrafraction motion also. CONCLUSIONS: Bladder volume variation will result in geographic miss in a high proportion of delivered bladder radiotherapy treatments. The A-POLO strategy can be used to correct for this and can be implemented from the first fraction of radiotherapy; thus, it is particularly suited to hypofractionated bladder radiotherapy regimens.
OBJECTIVE: To investigate the effect of reconstruction slice thickness on image quality at CT virtual cystoscopy (VC). METHODS: Pelvic CT examinations in bladder cancer patients were reconstructed at different slice thicknesses (0.6-5 mm) and intervals, and resulting VC images assessed. Quality indicators were ridging, holes, floaters and dimpling artefacts, tumour definition, and an overall score, ranked 1 (best) to 7 (worst). CT number and standard deviation (SD) for bladder contents and bladder wall were recorded. The mean SD was used as a measure of noise, and the contrast-to-noise ratio (CNR) was calculated as the CT number difference between them divided by the average image noise. The mean CNR across the three levels was used for analysis. Each qualitative image quality measure was compared with CT number, noise and CNR measurements. RESULTS: Dimpling artefacts increased with thinner slice reconstruction and correlated with increased noise, often resulting in poor tumour definition. The best overall image quality score was seen for VC images reconstructed at 1.2 mm slice thickness, probably because of the competing effects of spatial resolution and CNR. CONCLUSION: A slice thickness reconstruction <1.2 mm does not provide for better image quality at VC owing to the presence of increased noise.
INTRODUCTION: Metastases to the central nervous system may occur with tumours of any primary origin. Brain (cerebral) metastases may be either single or multiple, with or without disseminated disease elsewhere. Brain metastases may present with focal or generalised symptoms, although up to a third of patients may be asymptomatic. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of interventions for managing brain metastases in adults? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2007 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare Regulatory Agency (MHRA). RESULTS: We identified 18 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: corticosteroids; cytotoxic chemotherapy (systemic); radiation sensitisers plus whole-brain radiotherapy (external beam); surgery; radiosurgery; surgery plus radiosurgery; surgery plus radiosurgery plus whole-brain radiotherapy (external beam); surgery plus whole-brain radiotherapy (external beam); whole-brain radiotherapy (external beam); and whole-brain radiotherapy plus radiosurgery.
AIMS: Adaptive bladder radiotherapy, with plan of the day selection and plan library development based on individual filling patterns, has been previously modelled in patients receiving weekly hypofractionated treatment and improved geometric accuracy has been shown. The aim of this study was to assess the clinical implementation of the technique. MATERIALS AND METHODS: Conformal plans (with small, intermediate and large planning target volumes) were developed for 25 patients. After pre-treatment cone-beam computed tomography, the optimal plan of the day was selected and delivered by two trained observers. Independent off-line plan selection was also carried out. Concordance between the on-line and off-line selections, frequency of plan usage, target coverage and normal tissue sparing were assessed. RESULTS: Plan selection concordance was 91%. Fifty-five per cent of fractions were delivered using small or large plans. The mean coverage of the clinical target volume by the 95% isodose was 99%. The mean reduction in the volume of normal tissue treated to 95% of the prescription dose was 219 cm(3) compared with the previous institutional standard approach. CONCLUSIONS: Good concordance in plan selection is shown with clinical implementation of the adaptive strategy. Adequate target coverage was achieved with reduction in the volume of normal tissue irradiated to a high dose compared with the previous standard approach.
PURPOSE OF REVIEW: Primary melanomas originating from the gynaecological tract are rare and aggressive cancers. The 5-year survival is around 10%. The majority of tumours differ from cutaneous melanomas, which arise from the skin, by developing from melanocytes located in mucosal epithelium. The clinical behaviour, prognosis and the biology of mucosal melanomas are distinct from cutaneous melanomas. In this article, we summarize the current management of melanomas of the gynaecological tract (vulva, vagina, ovary and cervix) and discuss the progress in developing new treatments. RECENT FINDINGS: The management of mucosal melanomas has not changed substantially over the last decade and the prognosis remains poor. Surgery remains the primary treatment of choice in all localized melanomas of the genital tract. Radiotherapy and chemotherapy are options but have limited success for the majority of women. Activation of c-KIT occurs in vulvar melanomas. Clinical trials of targeted agents are underway. SUMMARY: As a result of the rarity of gynaecological tract melanomas, challenges associated with their anatomical locations and resistance to conventional radiotherapy and chemotherapy, this group of conditions remain difficult to treat and continue to have a poor prognosis. A greater understanding of the molecular profile of these cancers may provide promising targeted approaches.
OBJECTIVE: The implementation of plan of the day selection for patients receiving radiotherapy (RT) for bladder cancer requires efficient and confident decision-making. This article describes the development of a training programme and maintenance of competency. METHODS: Cone beam CT (CBCT) images acquired on patients receiving RT for bladder cancer were assessed to establish baseline competency and training needs. A training programme was implemented, and observers were asked to select planning target volumes (PTVs) on two groups of 20 patients' images. After clinical implementation, the PTVs chosen were reviewed offline, and an audit performed after 3 years. RESULTS: A mean of 73% (range, 53-93%) concordance rate was achieved prior to training. Subsequent to training, the mean score decreased to 66% (Round 1), then increased to 76% (Round 2). Six radiographers and two clinicians successfully completed the training programme. An independent observer reviewed the images offline after clinical implementation, and a 91% (126/139) concordance rate was achieved. During the audit, 125 CBCT images from 13 patients were reviewed by a single observer and concordance was 92%. CONCLUSION: Radiographer-led selection of plan of the day was implemented successfully with the use of a training programme and continual assessment. Quality has been maintained over a period of 3 years. ADVANCES IN KNOWLEDGE: The training programme was successful in achieving and maintaining competency for a plan of the day technique.
<h4>Aims</h4>To retrospectively review the toxicity and early outcome data from patients who have received stereotactic body radiotherapy (SBRT) for extracranial oligometastases at a single UK institution.<h4>Materials and methods</h4>Eligible patients had ≤3 extracranial metastases and performance status ≤2. Prior systemic therapy and radical treatment of oligometastastic relapse with any standard treatment modality was permitted. Patients with synchronous metastatic disease were excluded unless they had evidence of controlled primary disease after radical therapy. Follow-up consisted of clinical examination, biochemical and radiological assessments in accordance with standard clinical care. Progression events were defined using RECIST. Toxicity was evaluated using CTCAE v4.0. Local control, progression-free survival (PFS), freedom from widespread distant metastasis (defined as disease not amenable to further radical salvage therapy) and overall survival were calculated.<h4>Results</h4>Between July 2011 and April 2014, 73 patients with 87 metastases received SBRT (range 1-3 per patient). The median follow-up was 14.5 months (range 0-26.4). The median PFS was 14.5 months (1 year PFS 57%, 2 year 28%); 1 year overall survival 96%, 2 year 79.8%; 2 year local control 88%. At 2 years, 46% of patients were free from widespread distant metastases. No ≥ grade 3 acute or late toxicity was observed.<h4>Conclusion</h4>At this time point, observed toxicity is minimal with excellent local control rates. This promising treatment paradigm requires further investigation in the context of a randomised controlled trial to establish if the addition of SBRT to standard care improves survival outcomes.
<h4>Purpose</h4>Image guided adaptive radiation therapy offers individualized solutions to improve target coverage and reduce normal tissue irradiation, allowing the opportunity to increase the radiation tumor dose and spare normal bladder tissue.<h4>Methods and materials</h4>A library of 3 intensity modulated radiation therapy plans were created (small, medium, and large) from planning computed tomography (CT) scans performed at 30 and 60 minutes; treating the whole bladder to 52 Gy and the tumor to 70 Gy in 32 fractions. A "plan of the day" approach was used for treatment delivery. A post-treatment cone beam CT (CBCT) scan was acquired weekly to assess intrafraction filling and coverage.<h4>Results</h4>A total of 18 patients completed treatment to 70 Gy. The plan and treatment for 1 patient was to 68 Gy. Also, 1 patient's plan was to 70 Gy but the patient was treated to a total dose of 65.6 Gy because dose-limiting toxicity occurred before dose escalation. A total of 734 CBCT scans were evaluated. Small, medium, and large plans were used in 36%, 48%, and 16% of cases, respectively. The mean ± standard deviation rate of intrafraction filling at the start of treatment (ie, week 1) was 4.0 ± 4.8 mL/min (range 0.1-19.4) and at end of radiation therapy (ie, week 5 or 6) was 1.1 ± 1.6 mL/min (range 0.01-7.5; P=.002). The mean D98 (dose received by 98% volume) of the tumor boost and bladder as assessed on the post-treatment CBCT scan was 97.07% ± 2.10% (range 89.0%-104%) and 99.97% ± 2.62% (range 96.4%-112.0%). At a median follow-up period of 19 months (range 4-33), no muscle-invasive recurrences had developed. Two patients experienced late toxicity (both grade 3 cystitis) at 5.3 months (now resolved) and 18 months after radiation therapy.<h4>Conclusions</h4>Image guided adaptive radiation therapy using intensity modulated radiation therapy to deliver a simultaneous integrated tumor boost to 70 Gy is feasible, with acceptable toxicity, and will be evaluated in a randomized trial.
<h4>Aims</h4>Despite recent advances in the primary and secondary prevention of cervical cancer, a significant number of women present with or develop metastatic disease. There is currently no consensus on the standard of care for second-line systemic treatment of recurrent/metastatic cervical cancer. The purpose of this study was to evaluate the second-line systemic therapy used and the associated outcomes in a single cancer centre.<h4>Materials and methods</h4>A retrospective review of patients with cervical cancer who received one or more lines of treatment for recurrent or metastatic cervical cancer at the Royal Marsden Hospital between 2004 and 2014 was carried out. The primary objective was to establish the types of second-line systemic treatment used. Secondary end points included objective response rate, progression-free survival and overall survival after second-line therapy.<h4>Results</h4>In total, 75 patients were included in the study; 53 patients (70.7%) received second-line therapy for recurrent/metastatic disease. The most common second-line therapy was weekly paclitaxel (28.3%). Carboplatin-based chemotherapy (24.5%), targeted agent monotherapy within clinical trials (22.6%), docetaxel-based chemotherapy (13.2%), topotecan (9.4%) and gemcitabine (1.9%) were also used. The objective response rate to second-line therapy was 13.2%, which included three partial responses to carboplatin and paclitaxel, two partial responses to docetaxel-based chemotherapy, one partial response to weekly paclitaxel and one partial response to cediranib. Twenty-two patients (41.5%) achieved stable disease at 4 months. The median progression-free survival for women treated with second-line therapy was 3.2 months (95% confidence interval 2.1-4.3) and median overall survival was 9.3 months (95% confidence interval 6.4-12.5). Thirty-nine per cent of patients received third-line therapy.<h4>Conclusion</h4>Seventy per cent of patients treated with first-line systemic therapy for recurrent/metastatic cervical cancer subsequently received second-line treatment but response rates were poor. There remains no standard of care for second-line systemic therapy for advanced cervical cancer. Patients should be considered for clinical trials whenever feasible, including novel targeted agents and immunotherapy.
282 Background: The A-POLO strategy allows the optimal 'plan of the day' to be selected online for radiotherapy (RT) delivery. The methodology is implemented in a phase II study of patients with muscle-invasive bladder cancer who are not suitable for cystectomy/daily RT and are receiving hypofractionated RT. METHODS: Planning scans were performed at 0 and 30 minutes post void (CT0 and CT30). Three conformal plans were created (small, intermediate, large) ( Table ). Patients were prescribed 6Gy weekly for 5-6 weeks. A pre-RT cone beam CT (CBCT) scan and online set-up correction were performed. The plan giving the optimal target coverage was selected by 2 observers. Offline plan selection was also carried out by an independent observer. A post-RT CBCT was acquired to calculate the percentage of the CTV covered by 95% of the dose (V95). The mean A- POLO volume was compared to our previous institutional standard PTV (1.5cm isotropic margins) (PTViso). Outcome data were collected. RESULTS: A total of 77 RT fractions were delivered to 14 patients. The small plan was delivered for 38 (49%) fractions and the large for 6 (8%) fractions. The concordance rate between online and offline plan selection was 71/77 (92%). The mean CTV V95 was 99% (patient mean range 97-100%). The mean time between the pre- and post-treatment CBCT was 15 minutes. The mean reduction between PTViso and mean A-POLO PTV was 42% (range 16- 59%). 2 patients had grade (G) 3 (CTCv3.0) treatment-related acute toxicity. There have been no treatment-related G4 acute or G3 late toxicities. With a median follow-up of 7.3 months 10 patients are alive with 8 disease free (1 local and 1 distant relapse). CONCLUSIONS: Implementation of A-POLO RT is feasible, well tolerated, and associated with good concordance in 'plan of the day' selection. An individualized treatment plan can be delivered with each fraction to achieve a reduction in PTV compared to PTViso with maintenance of target coverage. [Table: see text] No significant financial relationships to disclose.
<h4>Purpose</h4>3D ultrasound (US) images of the uterus may be used to adapt radiotherapy (RT) for cervical cancer patients based on changes in daily anatomy. This requires accurate on-line segmentation of the uterus. The aim of this work was to assess the accuracy of Elekta's "Assisted Gyne Segmentation" (AGS) algorithm in semi-automatically segmenting the uterus on 3D transabdominal ultrasound images by comparison with manual contours.<h4>Materials & methods</h4>Nine patients receiving RT for cervical cancer were imaged with the 3D Clarity<sup>®</sup> transabdominal probe at RT planning, and 1 to 7 times during treatment. Image quality was rated from unusable (0)-excellent (3). Four experts segmented the uterus (defined as the uterine body and cervix) manually and using AGS on images with a ranking > 0. Pairwise analysis between manual contours was evaluated to determine interobserver variability. The accuracy of the AGS method was assessed by measuring its agreement with manual contours via pairwise analysis.<h4>Results</h4>35/44 images acquired (79.5%) received a ranking > 0. For the manual contour variation, the median [interquartile range (IQR)] distance between centroids (DC) was 5.41 [5.0] mm, the Dice similarity coefficient (DSC) was 0.78 [0.11], the mean surface-to-surface distance (MSSD) was 3.20 [1.8] mm, and the uniform margin of 95% (UM95) was 4.04 [5.8] mm. There was no correlation between image quality and manual contour agreement. AGS failed to give a result in 19.3% of cases. For the remaining cases, the level of agreement between AGS contours and manual contours depended on image quality. There were no significant differences between the AGS segmentations and the manual segmentations on the images that received a quality rating of 3. However, the AGS algorithm had significantly worse agreement with manual contours on images with quality ratings of 1 and 2 compared with the corresponding interobserver manual variation. The overall median [IQR] DC, DSC, MSSD, and UM95 between AGS and manual contours was 5.48 [5.45] mm, 0.77 [0.14], 3.62 [2.7] mm, and 5.19 [8.1] mm, respectively.<h4>Conclusions</h4>The AGS tool was able to represent uterine shape of cervical cancer patients in agreement with manual contouring in cases where the image quality was excellent, but not in cases where image quality was degraded by common artifacts such as shadowing and signal attenuation. The AGS tool should be used with caution for adaptive RT purposes, as it is not reliable in accurately segmenting the uterus on 'good' or 'poor' quality images. The interobserver agreement between manual contours of the uterus drawn on 3D US was consistent with results of similar studies performed on CT and MRI images.
<h4>Background and aim</h4>Worldwide, 1,470,900 women are diagnosed yearly with a gynecological malignancy (21,000 in the UK). Some patients treated with pelvic radiotherapy develop chronic changes in their bowel function. This systematic review summarizes current research on the impact of cancer treatment on the gut and vaginal microbiome in women with a gynecological malignancy.<h4>Methods</h4>The Preferred reporting Items for Systematic Reviews and Meta-analyses guidelines for systematic reviews were used to ensure transparent and complete reporting. Quantitative studies exploring the gut or vaginal microbiome in this patient cohort were included. Animal studies were excluded. There were no language restrictions.<h4>Results</h4>No studies examined the possible effects of surgery or chemotherapy for gynecological cancers on the gut or vaginal microbiome.Three prospective cohort studies were identified using sequencing of changes in the gut microbiome reporting on a total of 23 women treated for gynecological cancer. All studies included patients treated with radiotherapy with a dosage ranging from 43.0 to 54.0 Gy. Two studies assessed gastrointestinal toxicity formally; 8 women (57%) developed grade 2 or 3 diarrhea during radiotherapy. The outcomes suggest a correlation between changes in the intestinal microbiome and receiving radiotherapy and showed a decrease in abundance and diversity of the intestinal bacterial species. Before radiotherapy, those who developed diarrhea had an increased abundance of Bacteroides, Dialister, and Veillonella (P < 0.01), and a decreased abundance of Clostridium XI and XVIII, Faecalibacterium, Oscillibacter, Parabacteroides, Prevotella, and unclassified bacteria (P < 0.05).<h4>Conclusion</h4>The limited evidence to date implies that larger studies including both the vaginal and gut microbiome in women treated for a gynecological malignancy are warranted to explore the impact of cancer treatments on the microbiome and its relation to developing long-term gastrointestinal toxicity. This may lead to new avenues to stratify those at risk and explore personalized treatment options and prevention of gastrointestinal consequences of cancer treatments.
<h4>Purpose and objectives</h4>We report on the clinical outcomes of a phase 2 study assessing image guided hypofractionated weekly radiation therapy in bladder cancer patients unsuitable for radical treatment.<h4>Methods and materials</h4>Fifty-five patients with T2-T4aNx-2M0-1 bladder cancer not suitable for cystectomy or daily radiation therapy treatment were recruited. A "plan of the day" radiation therapy approach was used, treating the whole (empty) bladder to 36 Gy in 6 weekly fractions. Acute toxicity was assessed weekly during radiation therapy, at 6 and 12 weeks using the Common Terminology Criteria for Adverse Events version 3.0. Late toxicity was assessed at 6 months and 12 months using Radiation Therapy Oncology Group grading. Cystoscopy was used to assess local control at 3 months. Cumulative incidence function was used to determine local progression at 1 at 2 years. Death without local progression was treated as a competing risk. Overall survival was estimated using the Kaplan-Meier method.<h4>Results</h4>Median age was 86 years (range, 68-97 years). Eighty-seven percent of patients completed their prescribed course of radiation therapy. Genitourinary and gastrointestinal grade 3 acute toxicity was seen in 18% (10/55) and 4% (2/55) of patients, respectively. No grade 4 genitourinary or gastrointestinal toxicity was seen. Grade ≥3 late toxicity (any) at 6 and 12 months was seen in 6.5% (2/31) and 4.3% (1/23) of patients, respectively. Local control after radiation therapy was 92% of assessed patients (60% total population). Cumulative incidence of local progression at 1 year and 2 years for all patients was 7% (95% confidence interval [CI] 2%-17%) and 17% (95% CI 8%-29%), respectively. Overall survival at 1 year was 63% (95% CI 48%-74%).<h4>Conclusion</h4>Hypofractionated radiation therapy delivered weekly with a plan of the day approach offers good local control with acceptable toxicity in a patient population not suitable for radical bladder treatment.
<b>Background:</b> Therapeutic radiotherapy is an important treatment of pelvic cancers. Historically, low-fiber diets have been recommended despite a lack of evidence and potentially beneficial mechanisms of fiber.<b>Objective:</b> This randomized controlled trial compared low-, habitual-, and high-fiber diets for the prevention of gastrointestinal toxicity in patients undergoing pelvic radiotherapy.<b>Design:</b> Patients were randomly assigned to low-fiber [≤10 g nonstarch polysaccharide (NSP)/d], habitual-fiber (control), or high-fiber (≥18 g NSP/d) diets and received individualized counseling at the start of radiotherapy to achieve these targets. The primary endpoint was the difference between groups in the change in the Inflammatory Bowel Disease Questionnaire-Bowel Subset (IBDQ-B) score between the starting and nadir (worst) score during treatment. Other measures included macronutrient intake, stool diaries, and fecal short-chain fatty acid concentrations.<b>Results:</b> Patients were randomly assigned to low-fiber (<i>n</i> = 55), habitual-fiber (<i>n</i> = 55), or high-fiber (<i>n</i> = 56) dietary advice. Fiber intakes were significantly different between groups (<i>P</i> < 0.001). The difference between groups in the change in IBDQ-B scores between the start and nadir was not significant (<i>P</i> = 0.093). However, the change in score between the start and end of radiotherapy was smaller in the high-fiber group (mean ± SD: -3.7 ± 12.8) than in the habitual-fiber group (-10.8 ± 13.5; <i>P</i> = 0.011). At 1-y postradiotherapy (<i>n</i> = 126) the difference in IBDQ-B scores between the high-fiber (+0.1 ± 14.5) and the habitual-fiber (-8.4 ± 13.3) groups was significant (<i>P</i> = 0.004). No significant differences were observed in stool frequency or form or in short-chain fatty acid concentrations. Significant reductions in energy, protein, and fat intake occurred in the low- and habitual-fiber groups only.<b>Conclusions:</b> Dietary advice to follow a high-fiber diet during pelvic radiotherapy resulted in reduced gastrointestinal toxicity both acutely and at 1 y compared with habitual-fiber intake. Restrictive, non-evidence-based advice to reduce fiber intake in this setting should be abandoned. This trial was registered at clinicaltrials.gov as NCT 01170299.
OBJECTIVE: To describe and compare demographics and symptom presentation in Asian and Caucasian patients with acute coronary syndromes. DESIGN: Long-term prospective survey of symptom presentations in two racial groups. SETTING: A London hospital. PARTICIPANTS: A consecutive series of patients admitted to hospital with acute coronary syndromes between November 2001 and November 2005. MAIN OUTCOME MEASURE: Comparison of demographics and location, character, intensity and symptom distribution at presentation between Asian and Caucasian patients. RESULTS: Asian patients were younger than Caucasian patients (61 v 69 years, p<0.001) and more had diabetes (43% v 17%, p<0.001). Proportionally, more Asian patients had angina (51% v 37%, p<0.001), but more Caucasian patients had myocardial infarction (63% v 49%, p<0.001) and non-ST elevation infarcts (40% v 29%, p<0.001). Men reported smaller areas of discomfort than women. Asian patients more frequently reported discomfort over the rear of their upper bodies compared to Caucasian patients (46% v 25%, p<0.001) and radiation of discomfort to their arms and necks. A higher percentage of Asian than Caucasian patients demonstrated a "classical" location of symptoms (90% v 82%, p<0.001). Patients with diabetes were more likely to feel no discomfort. A higher percentage of Caucasian than Asian patients presented with "silent" events (13% v 6%, p>0.001), with age being a major determinant. CONCLUSION: Asian patients were younger, more likely to be diabetic and tended to report a higher intensity of pain and over a greater area of their body, and more frequent discomfort over the rear of their upper thorax than Caucasian patients.
Basal cell carcinomas are the most common form of skin cancer. Some develop into advanced cases not suitable for standard therapy. Vismodegib is the first-in-class oral hedgehog pathway inhibitor (which is dysregulated in 90% of basal cell carcinomas), and has demonstrated efficacy for advanced disease in clinical trials. An UK expert panel met to discuss management strategies for adverse events associated with vismodegib (most commonly taste disturbances, muscle cramps and alopecia). Managing patient expectations and implementing treatment breaks were considered important strategies. Quinine was useful to alleviate muscle cramps. For taste disturbances, food swaps alongside dietician referral were suggested. The experts concluded that these common adverse events can be successfully managed to allow optimum treatment duration of vismodegib.
Radiotherapy planning and delivery have dramatically improved in recent times. Imaging is key to a successful three-dimensional and increasingly four-dimensional based pathway with computed tomography embedded as the backbone modality. Computed tomography has significant limitations for many tumour sites where soft-tissue discrimination is suboptimal, and where magnetic resonance imaging (MRI) has largely superseded in the diagnostic arena. MRI is increasingly used together with computed tomography in the radiotherapy planning pathway and is now established as a prerequisite for several tumours. With the advent of combined MRI and linear accelerator (MR-linac) systems, a transition to MRI-based radiotherapy planning is becoming reality, with increasing experience and research involving these new platforms. In this overview, we aim to highlight how magnetic resonance-guided imaging has improved radiotherapy, using gynaecological malignancies to illustrate, in both external beam radiotherapy and image-guided brachytherapy, and will assess the early evidence for magnetic resonance-guided radiotherapy using combined MR-linac systems.
<b>Purpose:</b> MR-guided Radiation Therapy (MRgRT) allows for high-precision radiotherapy under real-time MR visualization. This enables margin reduction and subsequent dose escalation which may lead to higher tumor control and less toxicity. The Unity MR-linac (Elekta AB, Stockholm, Sweden) integrates a linear accelerator with a 1.5T diagnostic quality MRI and an online adaptive workflow. A prospective international registry was established to facilitate the evidence-based implementation of the Unity MR-linac into clinical practice, to systemically evaluate long-term outcomes, and to aid further technical development of MR-linac-based MRgRT. <b>Methods and Results:</b> In February 2019, the Multi-OutcoMe EvaluatioN of radiation Therapy Using the MR-linac study (MOMENTUM) started within the MR-linac Consortium. The MOMENTUM study is an international academic-industrial partnership between several hospitals and industry partner Elekta. All patients treated on the MR-linac are eligible for inclusion in MOMENTUM. For participants, we collect clinical patient data (e.g., patient, tumor, and treatment characteristics) and technical patient data which is defined as information generated on the MR-linac during treatment. The data are captured, pseudonymized, and stored in an international registry at set time intervals up to two years after treatment. Patients can choose to provide patient-reported outcomes and consent to additional MRI scans acquired on the MR-linac. This registry will serve as a data platform that supports multicenter research investigating the MR-linac. Rules and regulations on data sharing, data access, and intellectual property rights are summarized in an academic-industrial collaboration agreement. Data access rules ensure secure data handling and research integrity for investigators and institutions. Separate data access rules exist for academic and industry partners. This study is registered at ClinicalTrials.gov with ID: NCT04075305 (https://clinicaltrials.gov/ct2/show/NCT04075305). <b>Conclusion:</b> The multi-institutional MOMENTUM study has been set up to collect clinical and technical patient data to advance technical development, and facilitate evidenced-based implementation of MR-linac technology with the ultimate purpose to improve tumor control, survival, and quality of life of patients with cancer.
Ano-uro-genital (AUG) mucosal melanomas are rare cancers associated with poor outcomes and limited evidence-based management. The United Kingdom AUG mucosal melanoma guideline development group used an evidence-based systematic approach to make recommendations regarding the diagnosis, treatment and surveillance of patients diagnosed with AUG mucosal melanomas. The guidelines were sent for international peer review, and are accredited by The National Institute for Health and Clinical Excellence (NICE). A summary of the key recommendations is presented. The full documents are available on the Melanoma Focus website.
<h4>Purpose</h4>Adaptive radiation therapy strategies could account for interfractional uterine motion observed in patients with cervix cancer, but the current cone beam computed tomography (CBCT)-based treatment workflow is limited by poor soft-tissue contrast. The goal of the present study was to determine if ultrasound (US) could be used to improve visualization of the uterus, either as a single modality or in combination with CBCT.<h4>Methods and materials</h4>Interobserver uterine contour agreement and confidence were compared on 40 corresponding CBCT, US, and CBCT-US-fused images from 11 patients with cervix cancer. Contour agreement was measured using the Dice similarity coefficient (DSC) and mean contour-to-contour distance (MCCD). Observers rated their contour confidence on a scale from 1 to 10. Pairwise Wilcoxon signed-rank tests were used to measure differences in contour agreement and confidence.<h4>Results</h4>CBCT-US fused images had significantly better contour agreement and confidence than either individual modality (P < .05), with median (interquartile range [IQR]) values of 0.84 (0.11), 1.26 (0.23) mm, and 7 (2) for the DSC, MCCD, and observer confidence ratings, respectively. Contour agreement was similar between US and CBCT, with median (IQR) DSCs of 0.81 (0.17) and 0.82 (0.14) and MCCDs of 1.75 (1.15) mm and 1.62 (0.74) mm. Observers were significantly more confident in their US-based contours than in their CBCT-based contours (P < .05), with median (IQR) confidence ratings of 7 (2.75) versus 5 (4).<h4>Conclusions</h4>CBCT and US are complementary and improve uterine segmentation precision when combined. Observers could localize the uterus with a similar precision on independent US and CBCT images.
CT-based radiotherapy workflow is limited by poor soft tissue definition in the pelvis and reliance on rigid registration methods. Current image-guided radiotherapy and adaptive radiotherapy models therefore have limited ability to improve clinical outcomes. The advent of MRI-guided radiotherapy solutions provides the opportunity to overcome these limitations with the potential to deliver online real-time MRI-based plan adaptation on a daily basis, a true "plan of the day." This review describes the application of MRI guided radiotherapy in two pelvic tumour sites likely to benefit from this approach.
The stacked-ellipse (SE) algorithm was developed to rapidly segment the uterus on 3-D ultrasound (US) for the purpose of enabling US-guided adaptive radiotherapy (RT) for uterine cervix cancer patients. The algorithm was initialised manually on a single sagittal slice to provide a series of elliptical initialisation contours in semi-axial planes along the uterus. The elliptical initialisation contours were deformed according to US features such that they conformed to the uterine boundary. The uterus of 15 patients was scanned with 3-D US using the Clarity System (Elekta Ltd.) at multiple days during RT and manually contoured (n = 49 images and corresponding contours). The median (interquartile range) Dice similarity coefficient and mean surface-to-surface-distance between the SE algorithm and manual contours were 0.80 (0.03) and 3.3 (0.2) mm, respectively, which are within the ranges of reported inter-observer contouring variabilities. The SE algorithm could be implemented in adaptive RT to precisely segment the uterus on 3-D US.
<h4>Background and aim</h4>Long-term changes in gastrointestinal function impacting quality of life after treatment for cancer are common. Peer reviewed guidance to investigate and manage GI dysfunction following cancer treatment has been published. This study reviewed gastrointestinal symptoms of women previously treated for gynaecological cancer and considered whether suggested algorithms could be amended to optimise management for this cohort.<h4>Methods</h4>Demographic and clinical data recorded for patients attending a specialist consequences of cancer treatment gastroenterology service prospectively are reported using median and range. The Wilcoxon signed rank test analysed changes in symptoms between initial assessment to discharge from the service.<h4>Results</h4>Between April 2013 and March 2016, 220 women, with a median age of 57 years (range 24-83 years), treated for gynaecological cancer (cervical (50%)), endometrial (28%), ovarian (15%), vaginal or vulval (7%) attended. Twelve gastrointestinal symptoms were statistically significantly reduced by time of discharge from the specialist gastroenterology clinic including bowel frequency ≥ 4/day (88%), type 6 or 7 stool consistency (36%), urgency (31%) and incontinence (21%). General quality of life improved from a median score of 4 at first assessment to a median of 6 at discharge (p < 0.001). A median of four (range, 1-9) diagnoses were made.<h4>Conclusion</h4>Women with gastrointestinal symptoms after cancer treatment benefit from a systematic management approach. After excluding disease recurrence, a proposed investigational algorithm and the oncology team includes FBC, U&Es, LFTs, thyroid function test, vitamin B<sub>12</sub>, vitamin D, a hydrogen methane breath test and a SeHCAT scan. If rectal bleeding is present, iron studies, flexible sigmoidoscopy or colonoscopy should be performed. Patients with normal investigations or symptoms not responding to treatment require gastroenterology input.
<h4>Introduction</h4>IGRT in cervical cancer treatment delivery is complex due to significant target and organs at risk (OAR) motion. Implementing image assessment of soft-tissue target and OAR position to improve accuracy is recommended. We report the development and refinement of a training and competency programme (TCP), leading to on-line Radiation Therapist (RTT) led soft-tissue assessment, evaluated by a prospective audit.<h4>Methods and materials</h4>The TCP comprised didactic lectures and practical sessions, supported by a comprehensive workbook. The content was decided by a team comprised of Clinical Oncologists, RTTs, and Physicists. On completion of training, RTT soft-tissue review proficiency (after bony anatomy registration) was assessed against a clinician gold-standard from a database of 20 cervical cancer CBCT images. Reviews were graded pass or fail based on PTV coverage assessment and decision taken in concordance with the gold-standard. Parity was set at ≥80% agreement.The initial TCP (stage one) focussed on offline verification and decision making. Sixteen RTTs completed this stage, four achieved ≥80%. This was not sufficient to support clinical implementation.The TCP was redesigned, more stringent review guidelines and greater anatomy teaching was added. TCP stage two focussed on online verification and decision making supported by a decision flowchart. Twenty-one RTTs completed this TCP, all achieved ≥80%. This supported clinical implementation of RTT-led soft-tissue review under prospective audit conditions.The prospective audit was conducted between March 2017 and August 2017. Daily online review was performed by two trained RTTs. Online review and decision making proficiency was evaluated by a clinician.<h4>Results</h4>Thirteen patients were included in the audit. Daily online RTT-led IGRT was achieved for all 343 fractions. Two-hundred CBCT images were reviewed offline by the clinician; the mean number of reviews per patient was 15. 192/200 (96%) RTT image reviews were in agreement with clinician review, presenting excellent concordance.<h4>Discussion and conclusion</h4>Multidisciplinary involvement in training development, redesign of the TCP and inclusion of summative competency assessment were important factors to support RTT skill development. Consequently, RTT-led cervical cancer soft-tissue IGRT was clinically implemented in the hospital.
There is currently significant interest in the potential benefits of combining radiation and immune checkpoint blockade (ICB) to stimulate both regional and distant abscopal immune responses. In melanoma and lung cancer, patients who have received radiation therapy during ICB appear to have prolonged survival. The PLUMMB trial (Pembrolizumab in Muscle-invasive/Metastatic Bladder cancer) (NCT02560636) is a phase I study to test the tolerability of a combination of weekly radiation therapy with pembrolizumab in patients with metastatic or locally advanced urothelial cancer of the bladder. In the first dose-cohort, patients received pembrolizumab 100 mg 3-weekly, starting 2 weeks before commencing weekly adaptive bladder radiation therapy to a dose of 36 Gy in 6 fractions. The first dose-cohort was stopped after 5 patients, having met the predefined definition of dose-limiting toxicity. Three patients experienced grade 3 urinary toxicities, 2 of which were attributable to therapy. One patient experienced a grade 4 rectal perforation. In view of these findings, the trial has been paused and the protocol will be amended to reduce radiation therapy dose per fraction. The authors advise caution to those combining radiation therapy and ICB, particularly when radiation therapy is given at high dose per fraction for pelvic tumours. The PLUMMB trial met the protocol-defined definition of dose-limiting toxicity and will be amended to reduce radiation therapy dose.
<h4>Background and purpose</h4>Appropriate internal margins are essential to avoid a geographical miss in intensity-modulated radiation therapy (IMRT) for endometrial cancer (EC). This study evaluated interfraction target motion using rigid and non-rigid approximation strategies and calculated internal margins based on random and systematic errors using traditional rigid margin recipes. Dosimetric impact of target motion was also investigated.<h4>Materials and methods</h4>Cone beam CTs (CBCTs) were acquired days 1-4 and then weekly in 17 patients receiving adjuvant IMRT for EC; a total of 169 CBCTs were analysed. Interfraction motion for the clinical target volume vaginal vault and upper vagina (CTVv) was measured using bony landmarks and deformation vector field displacement (DVFD) within a 1 mm internal wall of CTVv. Patient and population systematic and random errors were estimated and margins calculated. Delivered dose to the CTVv and organs at risk was estimated.<h4>Results</h4>There was a significant difference in target motion assessment using the different registration strategies (p < 0.05). DVFD up to 30 mm occurred in the anterior/posterior direction, which was not accounted for in PTV margins using rigid margin recipes. Underdosing of CTVv D95% occurred in three patients who had substantial reductions in rectal volume (RV) during treatment. RV relative to the planning CT was moderately correlated with anterior/posterior displacement (r = 0.6) and mean relative RV during treatment was strongly correlated with mean relative RV at CBCT acquired days 1-3 (r = 0.8).<h4>Conclusion</h4>Complex and extensive geometric changes occur to the CTVv, which are not accounted for in margin recipes using rigid approximation. Contemporary margin recipes and adaptive treatment planning based on non-rigid approximation are recommended.
<h4>Background</h4>Computed tomography (CT) and magnetic resonance imaging (MRI) are the mainstay imaging modalities in radiotherapy planning. In MR-Linac treatment, manual annotation of organs-at-risk (OARs) and clinical volumes requires a significant clinician interaction and is a major challenge. Currently, there is a lack of available pre-annotated MRI data for training supervised segmentation algorithms. This study aimed to develop a deep learning (DL)-based framework to synthesize pelvic T<sub>1</sub>-weighted MRI from a pre-existing repository of clinical planning CTs.<h4>Methods</h4>MRI synthesis was performed using UNet++ and cycle-consistent generative adversarial network (Cycle-GAN), and the predictions were compared qualitatively and quantitatively against a baseline UNet model using pixel-wise and perceptual loss functions. Additionally, the Cycle-GAN predictions were evaluated through qualitative expert testing (4 radiologists), and a pelvic bone segmentation routine based on a UNet architecture was trained on synthetic MRI using CT-propagated contours and subsequently tested on real pelvic T<sub>1</sub> weighted MRI scans.<h4>Results</h4>In our experiments, Cycle-GAN generated sharp images for all pelvic slices whilst UNet and UNet++ predictions suffered from poorer spatial resolution within deformable soft-tissues (e.g. bladder, bowel). Qualitative radiologist assessment showed inter-expert variabilities in the test scores; each of the four radiologists correctly identified images as acquired/synthetic with 67%, 100%, 86% and 94% accuracy. Unsupervised segmentation of pelvic bone on T1-weighted images was successful in a number of test cases.<h4>Conclusion</h4>Pelvic MRI synthesis is a challenging task due to the absence of soft-tissue contrast on CT. Our study showed the potential of deep learning models for synthesizing realistic MR images from CT, and transferring cross-domain knowledge which may help to expand training datasets for 21 development of MR-only segmentation models.
Modern multimodality cancer treatment has led to a rise in cancer survivors, and by 2030 the survival rate is estimated to increase by 31.4%. This is an impressive survival statistic on which clinicians and services continue to build. One of the less well-acknowledged consequences of survivorship among health professionals and patients alike is female sexual dysfunction, despite it occurring in more than 60% of women diagnosed with cancer. The systematic assessment and management of late effects from cancer lack integration within current models of oncology follow-up. Although highly prevalent, issues linked to sexual health are often not addressed among survivors. This overview aims to focus on the sexual impact of gynaecological cancer treatment. Clinicians should raise the topic of the sexual consequences of cancer treatment as a legitimate aspect of survivorship and service provision. Increased focus on the sexual consequences of treatment and cancer survivorship may in time lead to greater clinical recognition, service development and, most importantly, increase research focused on the effective management of what remains a neglected aspect of cancer care.
<h4>Purpose</h4>High-field magnetic resonance-linear accelerators (MR-Linacs), linear accelerators combined with a diagnostic magnetic resonance imaging (MRI) scanner and online adaptive workflow, potentially give rise to novel online anatomic and response adaptive radiation therapy paradigms. The first high-field (1.5T) MR-Linac received regulatory approval in late 2018, and little is known about clinical use, patient tolerability of daily high-field MRI, and toxicity of treatments. Herein we report the initial experience within the MOMENTUM Study (NCT04075305), a prospective international registry of the MR-Linac Consortium.<h4>Methods and materials</h4>Patients were included between February 2019 and October 2020 at 7 institutions in 4 countries. We used descriptive statistics to describe the patterns of care, tolerability (the percentage of patients discontinuing their course early), and safety (grade 3-5 Common Terminology Criteria for Adverse Events v.5 acute toxicity within 3 months after the end of treatment).<h4>Results</h4>A total 943 patients participated in the MOMENTUM Study, 702 of whom had complete baseline data at the time of this analysis. Patients were primarily male (79%) with a median age of 68 years (range, 22-93) and were treated for 39 different indications. The most frequent indications were prostate (40%), oligometastatic lymph node (17%), brain (12%), and rectal (10%) cancers. The median number of fractions was 5 (range, 1-35). Six patients discontinued MR-Linac treatments, but none due to an inability to tolerate repeated high-field MRI. Of the 415 patients with complete data on acute toxicity at 3-month follow-up, 18 (4%) patients experienced grade 3 acute toxicity related to radiation. No grade 4 or 5 acute toxicity related to radiation was observed.<h4>Conclusions</h4>In the first 21 months of our study, patterns of care were diverse with respect to clinical utilization, body sites, and radiation prescriptions. No patient discontinued treatment due to inability to tolerate daily high-field MRI scans, and the acute radiation toxicity experience was encouraging.
<h4>Objectives</h4>Quantify target volume delineation uncertainty for CT/MRI simulation and MRI-guided adaptive radiotherapy in rectal cancer. Define optimal imaging sequences for target delineation.<h4>Methods</h4>Six experienced radiation oncologists delineated clinical target volumes (CTVs) on CT and 2D and 3D-MRI in three patients with rectal cancer, using consensus contouring guidelines. Tumour GTV (GTVp) was also contoured on MRI acquired week 0 and 3 of radiotherapy. A STAPLE contour was created and volume and interobserver variability metrics were analysed.<h4>Results</h4>There were statistically significant differences in volume between observers for CT and 2D-MRI-defined CTVs (<i>p</i> < 0.05). There was no significant difference between observers on 3D-MRI. Significant differences in volume were seen between observers for both 2D and 3D-MRI-defined GTVp at weeks 0 and 3 (<i>p</i> < 0.05). Good interobserver agreement (IOA) was seen for CTVs delineated on all imaging modalities with best IOA on 3D-MRI; median Conformity index (CI) 0.74 for CT, 0.75 for 2D-MRI and 0.77 for 3D-MRI. IOA of MRI-defined GTVp week 0 was better compared to CT; CI 0.58 for CT, 0.62 for 2D-MRI and 0.7 for 3D-MRI. MRI-defined GTVp IOA week three was worse compared to week 0.<h4>Conclusion</h4>Delineation on MRI results in smaller volumes and better IOA week 0 compared to CT. 3D-MRI provides the best IOA in CTV and GTVp. MRI-defined GTVp on images acquired week 3 showed worse IOA compared to week 0. This highlights the need for consensus guidelines in GTVp delineation on MRI during treatment course in the context of dose escalation MRI-guided rectal boost studies.<h4>Advances in knowledge</h4>Optimal MRI sequences for CT/MRI simulation and MRI-guided adaptive radiotherapy in rectal cancer have been defined.
The recent rise of deep learning (DL) and its promising capabilities in capturing non-explicit detail from large datasets have attracted substantial research attention in the field of medical image processing. DL provides grounds for technological development of computer-aided diagnosis and segmentation in radiology and radiation oncology. Amongst the anatomical locations where recent auto-segmentation algorithms have been employed, the pelvis remains one of the most challenging due to large intra- and inter-patient soft-tissue variabilities. This review provides a comprehensive, non-systematic and clinically-oriented overview of 74 DL-based segmentation studies, published between January 2016 and December 2020, for bladder, prostate, cervical and rectal cancers on computed tomography (CT) and magnetic resonance imaging (MRI), highlighting the key findings, challenges and limitations.
Radiation therapy (RT) is increasingly being used in gynecological cancer management. RT delivered with curative or palliative intent can be administered alone or combined with chemotherapy or surgery. Advanced treatment planning and delivery techniques such as intensity-modulated radiation therapy, including volumetric modulated arc therapy, and image-guided adaptive brachytherapy allow for highly conformal radiation dose delivery leading to improved tumor control rates and less treatment toxicity. Quality on-board imaging that provides accurate visualization of target and surrounding organs at risk is a critical feature of these advanced techniques. As soft tissue contrast resolution is superior with magnetic resonance imaging (MRI) compared to other imaging modalities, MRI has been used increasingly to delineate tumor from adjacent soft tissues and organs at risk from initial diagnosis to tumor response evaluation. Gynecological cancers often have poor contrast resolution compared to the surrounding tissues on computed tomography scan, and consequently the benefit of MRI is high. One example is in management of locally advanced cervix cancer where adaptive MRI guidance has been broadly implemented for adaptive brachytherapy. The role of MRI for external beam RT is also steadily increasing. MRI information is being used for treatment planning, predicting, and monitoring position shifts and accounting for tissue deformation and target regression during treatment. The recent clinical introduction of online MRI-guided radiation therapy (oMRgRT) could be the next step in high-precision RT. This technology provides a tool to take full advantage of MRI not only at the time of initial treatment planning but as well as for daily position verification and online plan adaptation. Cervical, endometrial, vaginal, and oligometastatic ovarian cancers are being treated on MRI linear accelerator systems throughout the world. This review summarizes the current state, early experience, ongoing trials, and future directions of oMRgRT in the management of gynecological cancers.
<h4>Aims</h4>Radiotherapy with radiosensitisation offers opportunity for cure with organ preservation in muscle-invasive bladder cancer (MIBC). Treatment response assessment and follow-up are reliant on regular endoscopic evaluation of the retained bladder. In this study we aim to determine the role of diffusion-weighted magnetic resonance imaging (DWI) and apparent diffusion coefficient (ADC) analysis to assess bladder radiotherapy response.<h4>Materials and methods</h4>Patients with T2-T4aN0-3M0 MIBC suitable for radical radiotherapy were recruited prospectively to an ethics approved protocol. Following transurethral resection of the bladder tumour and prior to any treatment, magnetic resonance imaging including DWI was performed on a 1.5T system using b values of 0, 100, 150, 250, 500, 750 s/mm<sup>2</sup>. DWI was repeated 3 months after completing radiotherapy. Cystoscopy and tumour site biopsy were undertaken following this. The response was dichotomised into response (<T2) or poor response (≥T2). Tumour region of interest was delineated on b750 s/mm<sup>2</sup> image and transferred to the ADC map to calculate per pixel ADC values for all b values (ADC<sub>all</sub>) and high b values (ADC<sub>b100</sub>). ADC mean, percentiles, skew, kurtosis and their change (ΔADC and %ΔADC) were determined. Threshold predictive of response with highest specificity was ascertained using receiver operating characteristic analysis.<h4>Results</h4>Thirty-four patients were evaluated. Response was associated with a significant increase in ΔADC mean compared with poor response at ΔADC<sub>all</sub> (0.57 × 10<sup>-3</sup> mm<sup>2</sup>/s versus -0.01 × 10<sup>-3</sup> mm<sup>2</sup>/s; P < 0.0001) and ΔADC<sub>b100</sub> (0.58 × 10<sup>-3</sup> mm<sup>2</sup>/s versus -0.10 x 10<sup>-3</sup> mm<sup>2</sup>/s; P = 0.007). A 48.50% increase in %ΔADC<sub>all</sub> mean was seen in response compared with a 1.37% decrease in poor response (P < 0.0001). This corresponded to a %ΔADC<sub>b100</sub> mean increase of 50.34% in response versus a 7.36% decrease for poor response (P < 0.0001). Significant area under the curve (AUC) values predictive of radiotherapy response were identified at ΔADC and %ΔADC for ADC<sub>all</sub> and ADC<sub>b100</sub> mean, 10th, 25th, 50th, 75th and 90th percentiles (AUC >0.9, P < 0.01). ΔADC<sub>all</sub> mean of 0.16 × 10<sup>-3</sup> mm<sup>2</sup>/s and ΔADC<sub>b100</sub> mean 0.12 × 10<sup>-3</sup> mm<sup>2</sup>/s predicted radiotherapy response with sensitivity/specificity/positive predictive value/negative predictive value of 92.9%/100.0%/100.0%/75.0% and 89.3%/100.0%/100.0%/66.7%, respectively.<h4>Conclusions</h4>Quantitative DWI analysis can successfully provide non-invasive assessment of bladder radiotherapy response. Multicentre validation is required before prospective testing to inform MIBC radiotherapy follow-up schedules and decision making.
<h4>Purpose</h4>Preoperative nodal staging is important for planning treatment in cervical cancer and endometrial cancer, but remains challenging. We compare nodal staging accuracy of <sup>18</sup>F-ethyl-choline-(FEC)-PET/CT, <sup>18</sup>F-fluoro-deoxy-glucose-(FDG)-PET/CT, and diffusion-weighted-MRI (DW-MRI) with conventional morphologic MRI.<h4>Experimental design</h4>A prospective, multicenter observational study of diagnostic accuracy for nodal metastases was undertaken in 5 gyne-oncology centers. FEC-PET/CT, FDG-PET/CT, and DW-MRI were compared with nodal size and morphology on MRI. Reference standard was strictly correlated nodal histology. Eligibility included operable cervical cancer stage ≥ 1B1 or endometrial cancer (grade 3 any stage with myometrial invasion or grade 1-2 stage ≥ II).<h4>Results</h4>Among 162 consenting participants, 136 underwent study DW-MRI and FDG-PET/CT and 60 underwent FEC-PET/CT. In 118 patients, 267 nodal regions were strictly correlated at histology (nodal positivity rate, 25%). Sensitivity per patient (<i>n</i> = 118) for nodal size, morphology, DW-MRI, FDG- and FEC-PET/CT was 40%*, 53%, 53%, 63%*, and 67% for all cases (*, <i>P</i> = 0.016); 10%, 10%, 20%, 30%, and 25% in cervical cancer (<i>n</i> = 40); 65%, 75%, 70%, 80% and 88% in endometrial cancer (<i>n</i> = 78). FDG-PET/CT outperformed nodal size (<i>P</i> = 0.006) and size ratio (<i>P</i> = 0.04) for per-region sensitivity. False positive rates were all <10%.<h4>Conclusions</h4>All imaging techniques had low sensitivity for detection of nodal metastases and cannot replace surgical nodal staging. The performance of FEC-PET/CT was not statistically different from other techniques that are more widely available. FDG-PET/CT had higher sensitivity than size in detecting nodal metastases. False positive rates were low across all methods. The low false positive rate demonstrated by FDG-PET/CT may be helpful in arbitration of challenging surgical planning decisions.
<h4>Background and purpose</h4>Magnetic resonance imaging integrated linear accelerator (MR-Linac) platforms enable acquisition of diffusion weighted imaging (DWI) during treatment providing potential information about treatment response. Obtaining DWI on these platforms is technically different from diagnostic magnetic resonance imaging (MRI) scanners. The aim of this project was to determine feasibility of obtaining DWI and calculating apparent diffusion coefficient (ADC) parameters longitudinally in rectal cancer patients on the MR-Linac.<h4>Materials and methods</h4>Nine patients undergoing treatment on MR-Linac had DWI acquired using b-values 0, 30, 150, 500 s/mm<sup>2</sup>. Gross tumour volume (GTV) and normal tissue was delineated on DWI throughout treatment and median ADC was calculated using an in-house tool (pyOsirix ®).<h4>Results</h4>Seven out of nine patients were included in the analysis; all demonstrated downstaging at follow-up. A total of 63 out of 70 DWI were analysed (7 excluded due to poor image quality). An increasing trend of ADC median for GTV (1.15 × 10<sup>-3</sup> mm<sup>2</sup>/s interquartile range (IQ): 1.05-1.17 vs 1.59 × 10<sup>-3</sup> mm<sup>2</sup>/s IQ: 1.37 - 1.64; <i>p = 0.0156</i>), correlating to treatment response. In comparison ADC median for normal tissue remained the same between first and last fraction (1.61 × 10<sup>-3</sup> mm<sup>2</sup>/s IQ: 1.56-1.71 vs 1.67 × 10<sup>-3</sup> mm<sup>2</sup>/s IQ: 1.37-2.00; p = 0.9375).<h4>Conclusions</h4>DWI assessment in rectal cancer patients on MR-Linac is feasible. Initial results provide foundations for further studies to determine DWI use for treatment adaptation in rectal cancer.
Basal cell carcinoma (BCC) is an increasingly common cancer. For high-risk BCCs, there are several treatment options, with similar efficacies. The current best practice in deciding upon a particular treatment is for a patient-centred approach. At present, there are few resources available for patients to assist their choice. This reduces patient autonomy and increases the burden on clinicians within clinic. Patient decision aids (PDAs) have been shown to increase patient autonomy and facilitate shared decision-making. Currently, there is no published PDA designed to facilitate the decision between surgical management or radiotherapy in high-risk BCCs. We developed a novel decision aid designed along the International Patient Decision Aid Standards to fill this clinical need, and evaluated its acceptance by both patients and clinicians. We describe the challenges faced at initial alpha and subsequent beta testing, and go on to validate our PDA with both the Decisional Conflict Scale and the nine-item Shared Decision Making Questionnaire (SDMQ9). We include an example of the PDA and encourage other units to modify the PDA for their own use.
<h4>Aims</h4>Neoadjuvant chemoradiotherapy followed by surgery is the mainstay of treatment for patients with rectal cancer. Standard clinical target volume (CTV) to planning target volume (PTV) margins of 10 mm are used to accommodate inter- and intrafraction motion of target. Treating on magnetic resonance-integrated linear accelerators (MR-linacs) allows for online manual recontouring and adaptation (MRgART) enabling the reduction of PTV margins. The aim of this study was to investigate motion of the primary CTV (CTVA; gross tumour volume and macroscopic nodes with 10 mm expansion to cover microscopic disease) in order to develop a simultaneous integrated boost protocol for use on MR-linacs.<h4>Materials and methods</h4>Patients suitable for neoadjuvant chemoradiotherapy were recruited for treatment on MR-linac using a two-phase technique; only the five phase 1 fractions on MR-linac were used for analysis. Intrafraction motion of CTVA was measured between pre-treatment and post-treatment MRI scans. In MRgART, isotropically expanded pre-treatment PTV margins from 1 to 10 mm were rigidly propagated to post-treatment MRI to determine overlap with 95% of CTVA. The PTV margin was considered acceptable if overlap was >95% in 90% of fractions. To understand the benefit of MRgART, the same methodology was repeated using a reference computed tomography planning scan for pre-treatment imaging.<h4>Results</h4>In total, nine patients were recruited between January 2018 and December 2020 with T3a-T4, N0-N2, M0 disease. Forty-five fractions were analysed in total. The median motion across all planes was 0 mm, demonstrating minimal intrafraction motion. A PTV margin of 3 and 5mm was found to be acceptable in 96 and 98% of fractions, respectively. When comparing to the computed tomography reference scan, the analysis found that PTV margins to 5 and 10 mm only acceptably covered 51 and 76% of fractions, respectively.<h4>Conclusion</h4>PTV margins can be reduced to 3-5 mm in MRgART for rectal cancer treatment on MR-linac within an simultaneous integrated boost protocol.
<h4>Background</h4>The majority of locally advanced cervical cancers (LaCC) are causally related to HPV. We sought to investigate the utility of an ultra-sensitive HPV-DNA next generation sequencing (NGS) assay-panHPV-detect-in LaCC treated with chemoradiotherapy, as a marker of treatment response and persistent disease.<h4>Method</h4>Serial blood samples were collected from 22 patients with LaCC before, during and after chemoradiation. The presence of circulating HPV-DNA was correlated with clinical and radiological outcomes.<h4>Results</h4>The panHPV-detect test demonstrated a sensitivity and specificity of 88% (95% CI-70-99%) and 100% (95% CI-30-100%), respectively, and correctly identified the HPV-subtype (16, 18, 45, 58). After a median follow up of 16 months, and three relapses all had detectable cHPV-DNA at 3 months post-CRT despite complete response on imaging. Another four patients with radiological partial or equivocal response and undetectable cHPV-DNA at the 3-month time point did not go on to develop relapse. All patients with radiological CR and undetectable cHPV-DNA at 3-months remained disease free.<h4>Conclusions</h4>These results demonstrate that the panHPV-detect test shows high sensitivity and specificity for detecting cHPV-DNA in plasma. The test has potential applications in assessment of the response to CRT and in monitoring for relapse, and these initial findings warrant validation in a larger cohort.
<h4>Purpose</h4>Radiation therapy is the key treatment for locally advanced cervical cancer. Organ motion presents a challenge to accurate targeting of external beam radiation therapy. The plan-of-the-day (PotD) adaptive approach is therefore an attractive option. We present our experience and the procedural steps required to implement PotD for cervix cancer.<h4>Methods and materials</h4>We reviewed relevant studies on organ motion and adaptive radiation therapy identified through a literature search and cross referencing. These included 10 dosimetric and 3 quality of life studies directly assessing the PotD approach to radiation therapy in cervix cancer.<h4>Results</h4>Studies show improvements in target coverage and reduction of dose received by normal tissues and suggest improved toxicity. Clinical implementation of PotD has been slow because of a number of difficulties and uncertainties, which we discuss with the aim of helping teams to implement PotD at their center.<h4>Conclusions</h4>The PotD approach improves dosimetry and may improve toxicity. We describe a framework to assist with practical implementation.
<h4>Objective</h4>This study aims to determine local treatment response and long-term survival outcomes in patients with localised muscle-invasive bladder cancer (MIBC) patients receiving neoadjuvant chemotherapy (NAC) using diffusion-weighted MRI (DWI) and apparent diffusion coefficient (ADC) analysis.<h4>Methods</h4>Patients with T2-T4aN0-3M0 bladder cancer suitable for NAC were recruited prospectively. DWI was performed prior to NAC and was repeated following NAC completion. Conventional response assessment was performed with cystoscopy and tumour site biopsy. Response was dichotomised into response (<T2) or poor response (≥T2). Patients proceeded to either radical cystectomy or chemo-radiotherapy as standard of care. Tumour ADC values were calculated for all b-values (ADC<sub>all</sub>) and high b-values (ADC<sub>b100</sub>). Mean ADC, percentiles, skew, kurtosis, and their change (ΔADC and %ΔADC) were determined. Threshold predictive of response with highest specificity was ascertained using receiver operating characteristic (ROC) analysis. Median overall survival (OS), bladder-cancer-specific survival (bCSS), progression-free survival (PFS), and time to cystectomy were estimated using Kaplan-Meier method. Significant area under the curve (AUC) cut points were used to determine relationship with long-term endpoints and were compared using log-rank test.<h4>Results</h4>Forty-eight patients (96 DWI) were evaluated. NAC response was associated with significant increase in mean ΔADC and %ΔADC compared to poor response (ΔADC<sub>all</sub> 0.32×10<sup>-3</sup> versus 0.11×10<sup>-3</sup> mm<sup>2</sup>/s; p=0.009, and %ΔADC<sub>all</sub> 21.70% versus 8.23%; p=0.013). Highest specificity predicting response was seen at 75th percentile ADC (AUC, 0.8; p=0.01). Sensitivity, specificity, positive predictive power, and negative predictive power of %ΔADC<sub>b100</sub> 75th percentile was 73.7%, 90.0%, 96.6%, and 52.9%, respectively. %ΔADC<sub>b100</sub> 75th percentile >15.5% was associated with significant improvement in OS (HR, 0.40; 95% CI, 0.19-0.86; p=0.0179), bCSS (HR, 0.26; 95% CI, 0.08-0.82; p=0.0214), PFS (HR, 0.16; 95% CI, 0.05-0.48; p=0.0012), and time to cystectomy (HR, 0.19; 95% CI, 0.07-0.47; p=0.0004).<h4>Conclusions</h4>Quantitative ADC analysis can successfully identify NAC response and improved long-term clinical outcomes. Multi-centre validation to assess reproducibility and repeatability is required before testing within clinical trials to inform MIBC treatment decision making.<h4>Advances in knowledge</h4>We successfully demonstrated that measured change in DWI can successfully identify NAC response and improved long-term survival outcomes.
<h4>Background</h4>High-risk HPV infection is responsible for >99% of cervix cancers (CC). In persistent infections that lead to cancer, the tumour breaches the basement membrane, releasing HPV-DNA into the bloodstream (cHPV-DNA). A next-generation sequencing assay (NGS) for detection of plasma HPV circulating DNA (cHPV-DNA) has demonstrated high sensitivity and specificity in patients with locally advanced cervix cancers. We hypothesised that cHPV-DNA is detectable in early invasive cervical cancers but not in pre-invasive lesions (CIN).<h4>Methods</h4>Blood samples were collected from patients with CIN (<i>n</i> = 52) and FIGO stage 1A-1B CC (<i>n</i> = 12) prior to treatment and at follow-up. DNA extraction from plasma, followed by NGS, was used for the detection of cHPV-DNA.<h4>Results</h4>None of the patients with pre-invasive lesions were positive for CHPV-DNA. In invasive tumours, plasma from one patient (10%) reached the threshold of positivity for cHPV-DNA in plasma.<h4>Conclusion</h4>Low detection of cHPV-DNA in early CC may be explained by small tumour size, poorer access to lymphatics and circulation, and therefore little shedding of cHPV-DNA in plasma at detectable levels. The detection rate of cHPV-DNA in patients with early invasive cervix cancer using even the most sensitive of currently available technologies lacks adequate sensitivity for clinical utility.
<h4>Background</h4>The effect of chemoradiation on the anti-cancer immune response is being increasingly acknowledged; however, its clinical implications in treatment responses are yet to be fully understood. Human papillomavirus (HPV)-driven malignancies express viral oncogenic proteins which may serve as tumor-specific antigens and represent ideal candidates for monitoring the peripheral T-cell receptor (TCR) changes secondary to chemoradiotherapy (CRT).<h4>Methods</h4>We performed intra-tumoral and pre- and post-treatment peripheral TCR sequencing in a cohort of patients with locally-advanced HPV16-positive cancers treated with CRT. An in silico computational pipeline was used to cluster TCR repertoire based on epitope-specificity and to predict affinity between these clusters and HPV16-derived epitopes.<h4>Results</h4>Intra-tumoral repertoire diversity, intra-tumoral and post-treatment peripheral CDR3β similarity clustering were predictive of response. In responders, CRT triggered an increase peripheral TCR clonality and clonal relatedness. Post-treatment expansion of baseline peripheral dominant TCRs was associated with response. Responders showed more baseline clustered structures of TCRs maintained post-treatment and displayed significantly more maintained clustered structures. When applying clustering by TCR-specificity methods, responders displayed a higher proportion of intra-tumoral TCRs predicted to recognise HPV16 peptides.<h4>Conclusions</h4>Baseline TCR characteristics and changes in the peripheral T-cell clones triggered by CRT are associated with treatment outcome. Maintenance and boosting of pre-existing clonotypes are key elements of an effective anti-cancer immune response driven by CRT, supporting a paradigm in which the immune system plays a central role in the success of CRT in current standard-of-care protocols.
<h4>Background and purpose</h4>Interfraction motion during cervical cancer radiotherapy is substantial in some patients, minimal in others. Non-adaptive plans may miss the target and/or unnecessarily irradiate normal tissue. Adaptive radiotherapy leads to superior dose-volume metrics but is resource-intensive. The aim of this study was to predict target motion, enabling patient selection and efficient resource allocation.<h4>Materials and methods</h4>Forty cervical cancer patients had CT with full-bladder (CT-FB) and empty-bladder (CT-EB) at planning, and daily cone-beam CTs (CBCTs). The low-risk clinical target volume (CTV<sub>LR</sub>) was contoured. Mean coverage of the daily CTV<sub>LR</sub> by the CT-FB CTV<sub>LR</sub> was calculated for each patient. Eighty-three investigated variables included measures of organ geometry, patient, tumour and treatment characteristics. Models were trained on 29 patients (171 fractions). The Two-CT multivariate model could use all available data. The Single-CT multivariate model excluded data from the CT-EB. A univariate model was trained using the distance moved by the uterine fundus tip between CTs, the only method of patient selection found in published cervix plan-of-the-day studies. Models were tested on 11 patients (68 fractions). Accuracy in predicting mean coverage was reported as mean absolute error (MAE), mean squared error (MSE) and R<sup>2</sup>.<h4>Results</h4>The Two-CT model was based upon rectal volume, dice similarity coefficient between CT-FB and CT-EB CTV<sub>LR</sub>, and uterine thickness. The Single-CT model was based upon rectal volume, uterine thickness and tumour size. Both performed better than the univariate model in predicting mean coverage (MAE 7 %, 7 % and 8 %; MSE 82 %<sup>2</sup>, 65 %<sup>2</sup>, 110 %<sup>2</sup>; R<sup>2</sup> 0.2, 0.4, -0.1).<h4>Conclusion</h4>Uterocervix motion is complex and multifactorial. We present two multivariate models which predicted motion with reasonable accuracy using pre-treatment information, and outperformed the only published method.
<h4>Purpose</h4>Owing to substantial interfraction motion in cervical cancer, plan-of-the-day (PotD) adaptive radiation therapy may be of benefit to patients. Implementation is limited by uncertainty over how to generate the planning target volumes (PTVs). We compared published methods on our own patients.<h4>Methods and materials</h4>Forty patients each had 3 planning scans with variable bladder filling and daily cone beam computed tomographies (cone beam CTs) during radiation therapy; 5 to 11 cone beam CTs were selected to represent interfraction motion. Clinical target volumes (CTVs) and organs at risk were contoured following EMBRACE-II guidelines. A literature search identified 30 adaptive and nonadaptive solutions to PTV generation, which we applied to our patients. PTV sizes and mean coverage of the daily CTV were determined. For 11 patients, the clinically implemented, subjectively edited plan library was also investigated.<h4>Results</h4>Eleven studies assessed 15 PotD strategies against nonadaptive comparators on a median of 14 patients (range, 9-23). Some PotD approaches applied margin recipes to the CTV on each planning scan, some modeled the CTV against bladder volume, and others applied incremental isotropic margins to the CTV with a single planning scan. Generally, coverage improved as PTV size increased. The fixed isotropic margin required to provide 100% coverage of all patients was 44 mm, with a mean PTV size of 3316 cm<sup>3</sup>. The PotD strategy with the best coverage was a 2-plan library formed by modeling the CTV against bladder volume with extrapolation; it provided 98% mean coverage with 1419-cm<sup>3</sup> mean PTV size. A 3-plan library consisting of the CTV on each planning scan with 10-mm margin provided 96% mean coverage with 1346-cm<sup>3</sup> mean PTV size. The clinically implemented solution that employed subjective extrapolation had mean 100% coverage and 1282-cm<sup>3</sup> PTV size on the 11-patient subset. Coverage provided by the best nonadaptive strategies was not statistically superior to the best PotD strategy (<i>P</i> = .13), but PTVs were larger (<i>P</i> = .02).<h4>Conclusions</h4>We identified a modeled 2-plan method and a simple 3-plan method, both of which provided excellent coverage with small PTVs compared with nonadaptive strategies.
<h4>Purpose</h4>We determine the maximum tolerated tumor-focused dose (MTD) for the radical treatment of muscle invasive bladder cancer enabled by image guided adaptive radiation therapy and long-term clinical outcomes.<h4>Methods and materials</h4>Fifty-nine patients with T2 to T4aN0M0 unifocal urothelial muscle invasive bladder cancer suitable for daily radical radiation therapy were recruited prospectively to an ethics-approved protocol (NCT01124682). The uninvolved bladder (PTV<sub>bladder</sub>) was planned to 52 Gy in 32 fractions. The bladder tumor (PTV<sub>tumor</sub>) was planned to an assigned dose level of 68, 70, 72, or 74 Gy. If organ at risk dose constraints were violated, then PTV<sub>tumor</sub> was planned to 64 Gy. Dose level allocation was determined by concurrent toxicity assessment of all previous patients recruited. Acute toxicity was evaluated using Common Terminology Criteria for Adverse Events v3.0; late toxicity was evaluated using Radiation Therapy Oncology Group criteria. The MTD was predefined as the highest dose level with an estimated probability of ≤ 15% ≥ G3 late toxicity and an observed rate of <50% acute G3 and <10% acute G4 toxicity.<h4>Results</h4>Twenty-six patients were assigned to 68 Gy, of whom 6 were planned to 64 Gy; 29 patients were assigned to 70 Gy of whom 1 was planned to 68 Gy, 2 patients were assigned and planned to 72 Gy; no patients were assigned to 74 Gy. Three patients did not complete the treatment as planned, of whom only 1 patient stopped treatment because dose-limiting toxicity occurred. The MTD was 70 Gy. Acute genito-urinary and gastro-intestinal G3 acute toxicity was seen in 19% and 7% of patients, respectively. No acute G4 genito-urinary or gastro-intestinal toxicity was seen. Late toxicity (any) G3 and G4 was seen in 14% and 2% of patients, respectively. The 5-year overall survival was 58% (95% CI, 44%-71%). The bladder preservation rate was 89% (95% CI, 88%-96%) with 6 patients not retaining native bladder function.<h4>Conclusions</h4>Bladder tumor-focused dose escalation to 70 Gy using image guided adaptive radiation therapy is feasible with acceptable toxicity. This dose level has been evaluated in a phase II randomized control trial (RAIDER NCT02447549).
<h4>Importance</h4>In 2018, the first online adaptive magnetic resonance (MR)-guided radiotherapy (MRgRT) system using a 1.5-T MR-equipped linear accelerator (1.5-T MR-Linac) was clinically introduced. This system enables online adaptive radiotherapy, in which the radiation plan is adapted to size and shape changes of targets at each treatment session based on daily MR-visualized anatomy.<h4>Objective</h4>To evaluate safety, tolerability, and technical feasibility of treatment with a 1.5-T MR-Linac, specifically focusing on the subset of patients treated with an online adaptive strategy (ie, the adapt-to-shape [ATS] approach).<h4>Design, setting, and participants</h4>This cohort study included adults with solid tumors treated with a 1.5-T MR-Linac enrolled in Multi Outcome Evaluation for Radiation Therapy Using the MR-Linac (MOMENTUM), a large prospective international study of MRgRT between February 2019 and October 2021. Included were adults with solid tumors treated with a 1.5-T MR-Linac. Data were collected in Canada, Denmark, The Netherlands, United Kingdom, and the US. Data were analyzed in August 2023.<h4>Exposure</h4>All patients underwent MRgRT using a 1.5-T MR-Linac. Radiation prescriptions were consistent with institutional standards of care.<h4>Main outcomes and measures</h4>Patterns of care, tolerability, and technical feasibility (ie, treatment completed as planned). Acute high-grade radiotherapy-related toxic effects (ie, grade 3 or higher toxic effects according to Common Terminology Criteria for Adverse Events version 5.0) occurring within the first 3 months after treatment delivery.<h4>Results</h4>In total, 1793 treatment courses (1772 patients) were included (median patient age, 69 years [range, 22-91 years]; 1384 male [77.2%]). Among 41 different treatment sites, common sites were prostate (745 [41.6%]), metastatic lymph nodes (233 [13.0%]), and brain (189 [10.5%]). ATS was used in 1050 courses (58.6%). MRgRT was completed as planned in 1720 treatment courses (95.9%). Patient withdrawal caused 5 patients (0.3%) to discontinue treatment. The incidence of radiotherapy-related grade 3 toxic effects was 1.4% (95% CI, 0.9%-2.0%) in the entire cohort and 0.4% (95% CI, 0.1%-1.0%) in the subset of patients treated with ATS. There were no radiotherapy-related grade 4 or 5 toxic effects.<h4>Conclusions and relevance</h4>In this cohort study of patients treated on a 1.5-T MR-Linac, radiotherapy was safe and well tolerated. Online adaptation of the radiation plan at each treatment session to account for anatomic variations was associated with a low risk of acute grade 3 toxic effects.