Fracture liaison services in Ireland-how do we compare to international standards?

In this first na tional survey of public hospitals in The Republic of Ireland, we found fracture liaison services (FLS) to be heterogeneous, limited in many cases and poorly supported. A national strategy is urgently needed to support the implementation and operation of an FLS, and thus help reduce the burden of fragility fractures for patients and the healthcare system. INTRODUCTION: Fragility/low-trauma fractures are a global concern, whose incidence is rising as the population ages. Many are preventable, and people with a prior fragility fracture are at particularly high risk of further fractures. This patient group is the target of the International Osteoporosis Foundation (IOF) Capture the Fracture campaign, advocating global adoption of fracture liaison services (FLS), with the aim of preventing secondary fragility fractures. We wished to determine the current availability and standards of an FLS in Ireland, ahead of the launch of a National FLS database. METHODS: We devised a questionnaire encompassing the thirteen IOF standards for an FLS and asked all 16 public hospitals with an orthopaedic trauma unit in Ireland, to complete for the calendar year 2019 in patients aged ≥ 50 years. RESULTS: All sites returned the questionnaire, i.e. 100% response rate. Nine hospitals stated that they have an FLS, additionally one non-trauma hospital running a FLS responded, and were included. These 10 FLS had identified and managed 3444 non-hip fractures in the year 2019. This figure represents 19% of the expected non-hip fragility fracture numbers occurring annually in Ireland. Implementation of the IOF standards was very variable. All sites reported being inadequately resourced to provide a high-quality service necessary to be effective. CONCLUSION: The existence and functioning of FLS in Ireland are heterogeneous and suboptimal. A national policy to support the implementation of this programme in line with international standards of patient care is urgently needed.

Integrating the patients' voice in designing and delivering a research study: The Yorkshire Cancer Research funded PREHABS study's experience.

INTRODUCTION: Engaging with patients when designing a clinical or research project is beneficial; feedback from the intended audience provides invaluable insight form the patients' perspective. Working with patients can result in developing successful research grants and interventions. The benefit of including the voice of the patient in the Yorkshire Cancer Research funded PREHABS study is described in this article. METHODS: Patients were included in the PREHABS study from inception to completion. The Theory of Change methodology was used to provide a framework to implement patient feedback to refine the study intervention. RESULTS: In total, 69 patients engaged with the PREHABS project. Two patients were recruited as co-applicants on the grant and were members on the Trial Management Group. Six patients attended the pre application workshop and provided feedback on their lived experiences of being a lung cancer patient. Commentary from the patients influenced the interventions selected and the design of the prehabs study. Following ethical approval (21/EE/0048) and informed written consent, 61 patients were recruited into the PREHABS study between October 2021 and November 2022. The breakdown of recruited patients was 19 males: mean age 69.1 years (SD 8.91) and 41 females; mean age 74.9 years (SD 8.9). CONCLUSION: It is practicable and beneficial to include patients at all stages of designing and delivering a research study. Patient feedback can help refine the study interventions to allow for maximum acceptance, recruitment and retention. IMPLICATIONS FOR PRACTICE: Including patients in the design of radiotherapy research studies can provide invaluable insight that can support the selection and delivery of interventions that are acceptable to the patient cohort.

Prehabilitation and Rehabilitation for Patients with Lung Cancer: A Review of Where we are Today.

Lung cancer is the third most common type of cancer in the UK, with nearly 50 000 new cases diagnosed a year. Treatments for lung cancer have improved in recent years with the advent of new surgical and radiotherapy techniques and the increased use of immunotherapies. These advances have resulted in increasing numbers of patients surviving beyond the completion of their treatment. Lung cancer patients are now not dying from their cancer diagnosis, but from other co-existing pathologies. Lung cancer patients commonly present with multiple comorbidities. Mitigating the effects of poor lifestyles and changing behaviours may improve the efficacy of treatments, reduce side-effects and improve the quality of life for lung cancer patients. Published evidence supports the use of interventions to manage behavioural habits, to optimise the health of patients. There is no consensus as to what, when or how to embed these into the patient pathway. Supporting patients before, during and after their cancer treatments to increase activity, eat well and stop smoking have been seen to decrease side-effects and improve patient outcomes and wellbeing. The challenge is to provide a package of interventions that is acceptable to patients and fits within the patient pathway so as not to conflict with diagnostic and therapeutic activities. This article reviews where we are today with providing behavioural support to optimise the health of lung cancer patients undergoing treatment.

UK 2022 Consensus on Normal Tissue Dose-Volume Constraints for Oligometastatic, Primary Lung and Hepatocellular Carcinoma Stereotactic Ablative Radiotherapy.

The use of stereotactic ablative radiotherapy (SABR) in the UK has expanded over the past decade, in part as the result of several UK clinical trials and a recent NHS England Commissioning through Evaluation programme. A UK SABR Consortium consensus for normal tissue constraints for SABR was published in 2017, based on the existing literature at the time. The published literature regarding SABR has increased in volume over the past 5 years and multiple UK centres are currently working to develop new SABR services. A review and update of the previous consensus is therefore appropriate and timely. It is hoped that this document will provide a useful resource to facilitate safe and consistent SABR practice.

The Impact of Intra-thoracic Anatomical Changes upon the Delivery of Lung Stereotactic Ablative Radiotherapy.

AIMS: So far, the impact of intra-thoracic anatomical changes (ITACs) on patients treated with stereotactic ablative radiotherapy (SABR) for early-stage non-small cell lung cancer is unknown. Studying these is important, as ITACs have the potential to impact the workflow and reduce treatment quality. The aim of this study was to assess and categorise ITACs, as detected on cone beam computed tomography scans (CBCT), and their subsequent impact upon treatment in lung cancer patients treated with SABR. MATERIALS AND METHODS: CBCTs from 100 patients treated with SABR for early non-small cell lung cancer were retrospectively reviewed. The presence of the following ITACs was assessed: atelectasis, infiltrative change, pleural effusion, baseline shift and gross tumour volume (GTV) increase and decrease. ITACs were graded using a traffic light protocol. This was adapted from a tool previously developed to assesses potential target undercoverage or organ at risk overdose. The frequency of physics or clinician review was noted. A linear mixed effects model was used to assess the relationship between ITAC grade and set-up time (time from first CBCT to beam delivery). RESULTS: ITACs were observed in 22% of patients. Twenty-one per cent of these were categorised as 'red', implying a risk of underdosage to the GTV. Most were 'yellow' (51%), indicating little impact upon planning target volume coverage of the GTV. Physics or clinician review was required in 10% of all treatment fractions overall. Three patients needed their treatment replanned. The mixed effect model analysis showed that ITACs cause a significant prolongation of set-up time (Χ2(3) = 9.22, P = 0.02). CONCLUSION: Most ITACs were minor, but associated with unplanned physics or clinician review, representing a potentially significant resource burden. ITACs also had a significant impact upon set-up time, with consequences for the wider workflow and intra-fraction motion. Detailed guidance on the management of ITACs is needed to provide support for therapeutic radiographers delivering lung SABR.

Cardiovascular mortality and morbidity following radical radiotherapy for lung cancer: Is cardiovascular death under-reported?

BACKGROUND: Lung cancer is the most common malignancy worldwide. Radical radiotherapy is an essential treatment in the management of early and locally advanced lung cancer. Cardiac events are known to occur following radical radiotherapy for lung cancer. This study examines the burden of cardiac events post radiotherapy, and estimates the accuracy of death certification in patients who received radical radiotherapy for lung cancer. METHODS: We conducted a retrospective observational cohort study for all patients receiving radical radiotherapy for non-small cell lung cancer (NSCLC) at a large cancer centre between 01/01/2010 to 31/12/2016. Baseline cardiovascular disease and cancer status and treatment data were collected, along with hospital admission data and documented cause of death from the national registry for a median follow-up period of 34 months. RESULTS: Of 1224 patients included in the analysis, 378 (30.9%) patients had cardiovascular disease at baseline, including 140 (11.4%) with prior myocardial infarction. In the 846 patients without known cardiovascular disease, 451 (53.3%) had a QRISK2 predicted 10-year cardiovascular risk >20% over 10 years. During follow-up, 215 hospitalisations occurred (Incidence rate 6.2 per hundred patient years) which were classified as primarily cardiac, and 622 patients died (18 per 100 patient-years). However, death certificates stated a primary cardiac cause of death in only 33 cases (5.3% of deaths). Notably, 29% of patients dying out of hospital and certified as cancer death did not have documented cancer relapse prior to death, and 61% had no community palliative care input prior to death, implying these events may have been sudden and unexpected. CONCLUSION: There is a high prevalence of baseline cardiovascular disease in people undergoing radiotherapy for NSCLC, accompanied by significant rates of post-radiotherapy cardiovascular hospitalisation. However, only a small proportion of deaths are attributed to cardiovascular disease, together with the large amount of sudden deaths observed, this suggests that cardiovascular death is greatly under-reported in official statistics.

Reduced Fractionation in Lung Cancer Patients Treated with Curative-intent Radiotherapy during the COVID-19 Pandemic.

Patients treated with curative-intent lung radiotherapy are in the group at highest risk of severe complications and death from COVID-19. There is therefore an urgent need to reduce the risks associated with multiple hospital visits and their anti-cancer treatment. One recommendation is to consider alternative dose-fractionation schedules or radiotherapy techniques. This would also increase radiotherapy service capacity for operable patients with stage I-III lung cancer, who might be unable to have surgery during the pandemic. Here we identify reduced-fractionation for curative-intent radiotherapy regimes in lung cancer, from a literature search carried out between 20/03/2020 and 30/03/2020 as well as published and unpublished audits of hypofractionated regimes from UK centres. Evidence, practical considerations and limitations are discussed for early-stage NSCLC, stage III NSCLC, early-stage and locally advanced SCLC. We recommend discussion of this guidance document with other specialist lung MDT members to disseminate the potential changes to radiotherapy practices that could be made to reduce pressure on other departments such as thoracic surgery. It is also a crucial part of the consent process to ensure that the risks and benefits of undergoing cancer treatment during the COVID-19 pandemic and the uncertainties surrounding toxicity from reduced fractionation have been adequately discussed with patients. Furthermore, centres should document all deviations from standard protocols, and we urge all colleagues, where possible, to join national/international data collection initiatives (such as COVID-RT Lung) aimed at recording the impact of the COVID-19 pandemic on lung cancer treatment and outcomes.

Re-irradiation for Locally Recurrent Lung Cancer: Evidence, Risks and Benefits.

In spite of recent improvements in both the technical delivery of radiotherapy and systemic therapy in the treatment of non-small cell lung cancer, local recurrence rates after radiotherapy remain a significant challenge. In the setting of local relapse after radiotherapy, treatments such as surgical resection or radiofrequency ablation are often not appropriate owing to disease and patient factors. Re-irradiation may be a potential treatment option. This overview considers the published evidence and potential treatment strategies.

Effectiveness of Respiratory-gated Positron Emission Tomography/Computed Tomography for Radiotherapy Planning in Patients with Lung Carcinoma - A Systematic Review.

AIMS: A systematic review of the literature evaluating the clinical use of respiratory-gated (four-dimensional; 4D) fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) compared with non-gated (three-dimensional; 3D) PET/CT for radiotherapy planning in lung cancer. MATERIALS AND METHODS: A search of MEDLINE, Cochrane, Web of Science, SCOPUS and clinicaltrials.gov databases was undertaken for articles comparing 3D and 4D PET/CT tumour volume or 4D PET/CT for radiotherapy planning. PRISMA guidelines were followed. RESULTS: Thirteen studies compared tumour volumes at 3D and 4D PET/CT; eight reported significantly smaller volumes (6.9-44.5%), three reported significantly larger volumes at 4D PET/CT (16-50%), one reported no significant difference and one reported mixed findings. Six studies, including two that reported differences in tumour volumes, compared target volumes or studied geographic misses. 4D PET/CT target volumes were significantly larger (19-40%) when compared with 3D PET/CT in all but one study, where they were smaller (3.8%). One study reported no significance in 4D PET/CT target volumes when compared with 4D CT, whereas another study reported significantly larger volumes (38.7%). CONCLUSION: The use of 4D PET/CT leads to differences in target volume delineation compared with 3D PET/CT. These differences vary depending upon technique and the clinical impact currently remains uncertain. Correlation of pretreatment target volumes generated at 3D and 4D PET/CT with postsurgical histology would be ideal but technically challenging. Evaluation of patient outcomes based on 3D versus 4D PET/CT derived treatment volumes warrants further investigation.

SYSTEMS-2: A randomised phase II study of radiotherapy dose escalation for pain control in malignant pleural mesothelioma.

SYSTEMS-2 is a randomised study of radiotherapy dose escalation for pain control in 112 patients with malignant pleural mesothelioma (MPM). Standard palliative (20 Gy/5#) or dose escalated treatment (36 Gy/6#) will be delivered using advanced radiotherapy techniques and pain responses will be compared at week 5. Data will guide optimal palliative radiotherapy in MPM.

UK Consensus on Normal Tissue Dose Constraints for Stereotactic Radiotherapy.

Six UK studies investigating stereotactic ablative radiotherapy (SABR) are currently open. Many of these involve the treatment of oligometastatic disease at different locations in the body. Members of all the trial management groups collaborated to generate a consensus document on appropriate organ at risk dose constraints. Values from existing but older reviews were updated using data from current studies. It is hoped that this unified approach will facilitate standardised implementation of SABR across the UK and will allow meaningful toxicity comparisons between SABR studies and internationally.

Statistical modeling of biomedical corpora: mining the Caenorhabditis Genetic Center Bibliography for genes related to life span.

BACKGROUND: The statistical modeling of biomedical corpora could yield integrated, coarse-to-fine views of biological phenomena that complement discoveries made from analysis of molecular sequence and profiling data. Here, the potential of such modeling is demonstrated by examining the 5,225 free-text items in the Caenorhabditis Genetic Center (CGC) Bibliography using techniques from statistical information retrieval. Items in the CGC biomedical text corpus were modeled using the Latent Dirichlet Allocation (LDA) model. LDA is a hierarchical Bayesian model which represents a document as a random mixture over latent topics; each topic is characterized by a distribution over words. RESULTS: An LDA model estimated from CGC items had better predictive performance than two standard models (unigram and mixture of unigrams) trained using the same data. To illustrate the practical utility of LDA models of biomedical corpora, a trained CGC LDA model was used for a retrospective study of nematode genes known to be associated with life span modification. Corpus-, document-, and word-level LDA parameters were combined with terms from the Gene Ontology to enhance the explanatory value of the CGC LDA model, and to suggest additional candidates for age-related genes. A novel, pairwise document similarity measure based on the posterior distribution on the topic simplex was formulated and used to search the CGC database for "homologs" of a "query" document discussing the life span-modifying clk-2 gene. Inspection of these document homologs enabled and facilitated the production of hypotheses about the function and role of clk-2. CONCLUSION: Like other graphical models for genetic, genomic and other types of biological data, LDA provides a method for extracting unanticipated insights and generating predictions amenable to subsequent experimental validation.

Pitfalls and Challenges to Consider before Setting up a Lung Cancer Intensity-modulated Radiotherapy Service: A Review of the Reported Clinical Experience.

Intensity-modulated radiotherapy (IMRT) is being increasingly used for the treatment of non-small cell lung cancer (NSCLC), despite the absence of published randomised controlled trials. Planning studies and retrospective series have shown a decrease in known predictors of lung toxicity (V20 and mean lung dose) and the maximum spinal cord dose. Potential dosimetric advantages, accessibility of technology, a desire to escalate dose or a need to meet normal organ dose constraints are some of the factors recognised as supporting the use of IMRT. However, IMRT may not be appropriate for all patients being treated with radical radiotherapy. Unique problems with using IMRT for NSCLC include organ and tumour motion because of breathing and the potential toxicity from low doses of radiotherapy to larger amounts of lung tissue. Caution should be exercised as there is a paucity of prospective data regarding the efficacy and safety of IMRT in lung cancer when compared with three-dimensional conformal radiotherapy and IMRT data from other cancer sites should not be extrapolated. This review looks at the use of IMRT in NSCLC, addresses the challenges and highlights the potential benefits of using this complex radiotherapy technique.

Stereotactic Ablative Radiotherapy (SABR) in Patients with Medically Inoperable Peripheral Early Stage Lung Cancer: Outcomes for the First UK SABR Cohort.

AIMS: To report outcomes for the first UK cohort treated for early stage peripheral lung cancer using stereotactic ablative radiotherapy (SABR). MATERIALS AND METHODS: Patients were included who received SABR between May 2009 and May 2012. Electronic medical records were reviewed for baseline characteristics, treatment details and outcomes. Patients were treated according to the UK SABR Consortium Guidelines. Univariate and multivariate Cox regression was used to determine factors that influenced overall survival and local control. RESULTS: In total, 273 patients received SABR for 288 lesions in the time period examined. The median follow-up was 19.7 months. The median overall survival for all patients was 27.3 months, with 1, 2 and 3 year overall survival of 78.0, 54.9 and 38.6%, respectively. The 1, 2 and 3 year rates of local control were 98.2, 95.7 and 95.7%, respectively. All patients completed the planned course of treatment and rates of Common Toxicity Criteria grade 3+ toxicity were low. On multivariate analysis, patients with Medical Research Council (MRC) breathlessness scores of 3-5 had worse overall survival compared with patients with scores of 1-2 (hazard ratio: 2.10; 95% confidence interval: 1.25-3.59) and the presence of histological diagnosis conferred improved overall survival (hazard ratio: 0.54; 95% confidence interval: 0.31-0.93), probably reflecting that patients who are considered well enough to undergo biopsy are generally fitter overall. No factors were identified that significantly influenced local control. CONCLUSIONS: SABR is an effective and well-tolerated treatment option for patients with early stage peripheral lung cancer who are not suitable for surgery. No patient cohort was identified in whom SABR was considered inappropriate. This series adds to the existing positive data that support SABR for this patient group.

The SABRTooth feasibility trial protocol: a study to determine the feasibility and acceptability of conducting a phase III randomised controlled trial comparing stereotactic ablative radiotherapy (SABR) with surgery in patients with peripheral stage I non-small cell lung cancer (NSCLC) considered to be at higher risk of complications from surgical resection.

BACKGROUND: Stage I non-small cell lung cancer (NSCLC) is potentially curable, and surgery is considered to be the standard of care for patients with good performance status and minimal co-morbidity. However, a significant proportion of patients with stage I NSCLC have a poorer performance status and significant medical co-morbidity that make them at higher risk of morbidity and mortality from surgery. Stereotactic ablative radiotherapy (SABR), which uses modern radiotherapeutic techniques to deliver large doses of radiation, has shown superiority over conventional radiotherapy in terms of local control and toxicity and is a standard of care for patients with stage I NSCLC who are at too high risk for surgery. However, it is not known whether surgery or SABR is the most effective in patients with stage I NSCLC who are suitable for surgery but are less fit and at higher risk surgical complications. Previous randomised studies have failed to recruit in this setting, and therefore, a feasibility study is required to see whether a full randomised control trial would be possible. METHODS/DESIGN: SABRTooth is a UK-based, multi-centre, open-label, two-group individually (1:1) randomised controlled feasibility study in patients with peripheral stage I NSCLC considered to be at higher risk from surgical resection. The study will assess the feasibility of conducting a definitive large-scale phase III trial. The primary objective is to assess recruitment rates to provide evidence that, when scaled up, recruitment to a large phase III trial would be possible; the target recruitment being 54 patients in total, over a 21-month period. There are multiple secondary and exploratory objectives designed to explore the optimum recruitment and data collection strategies to help optimise the design of a future phase III trial. DISCUSSION: To know whether SABR is a better, equivalent or inferior alternative to surgery for higher risk patients is a key question in lung cancer. Other studies comparing SABR to surgery have closed early due to poor recruitment, and therefore, the SABRTooth feasibility study has been designed around the UK National Health Service (NHS) cancer pathway incorporating many design features in order to maximise recruitment for a future definitive phase III trial. TRIAL REGISTRATION: controlled-trials.com ISRCTN13029788.

Erratum to: The SABRTooth feasibility trial protocol: a study to determine the feasibility and acceptability of conducting a phase III randomised controlled trial comparing stereotactic ablative radiotherapy (SABR) with surgery in patients with peripheral stage I non-small cell lung cancer (NSCLC) considered to be at higher risk of complications from surgical resection.

[This corrects the article DOI: 10.1186/s40814-016-0046-2.].

Stereotactic ablative body radiotherapy for lung cancer.

Lung stereotactic ablative radiotherapy (SABR) is a method of delivering high 'ablative' doses of radiotherapy to tumours in the lung. It was developed at the Karolinska Institute in the early 1990s using the methods established in cranial radiosurgery with multiple beams prescribed to an isodose and using a custom designed stereotactic body frame for immobilisation. Since then, aligned with the advances in radiotherapy technology and techniques (e.g. four-dimensional computed tomography simulation and image-guided radiotherapy), there has been a rapid increase in the use of lung SABR for both early stage lung cancer and lung metastases. For peripheral primary lung cancers less than 5 cm in diameter, high rates of local control and low levels of acute and late toxicity are consistently reported in the published literature. Compared with historical control rates of stage I lung cancers treated with conventionally fractionated radiotherapy, SABR seems to offer higher rates of local control, lower levels of acute toxicity and a better quality of life after treatment. However, the full results of randomised controlled trials of SABR versus conventionally fractionated are awaited and will provide higher-level evidence. For central lung tumours, very high SABR doses can be associated with significant toxicity. Dose-adapted fractionation schedules seem to have much lower rates of toxicity and prospective trials, including the completed RTOG 0813 study and the on-going EORTC LUNGTEC study, should provide further evidence of safety and establish organ at risk tolerances. SABR can also be used for tumours metastatic to the lung with high rates of local control and is a reasonable alternative to surgery in selected patients. Going forward, prospective trials are underway to establish the safety and efficacy of SABR in oligometastatic disease. Population-based outcomes will be crucial in supporting/establishing SABR as the treatment of choice in medically inoperable patients with peripheral stage I lung cancers. Randomised phase III trials will hopefully extend the evidence base and show the safety and the utility of SABR in early central tumours and oligometastatic disease.

The Effect of Dose and Quality Assurance in Early Prostate Cancer Treated with Low Dose Rate Brachytherapy as Monotherapy.

AIMS: To examine the relationship between post-implant computed tomography dosimetry and long-term prostate-specific antigen relapse-free survival in patients treated with iodine 125 (I-125) low dose rate prostate brachytherapy as monotherapy and, second, to audit recent practice against Royal College of Radiologists' (RCR) guidelines after the re-introduction of post-implant dosimetry for all patients in our centre. MATERIALS AND METHODS: Between March 1995 and September 2007, 2157 consecutive patients with localised prostate cancer underwent I-125 permanent prostate brachytherapy as monotherapy in a single UK centre. All patients were transrectal ultrasound planned delivering a 145 Gy (TG 43) minimum peripheral dose. None received supplemental external beam radiotherapy. Post-implant computed tomography-based dosimetry was undertaken between 4 and 6 weeks after treatment and was available for 711 (33%). Outcomes were analysed in terms of the relationship of D90 to prostate-specific antigen relapse-free survival (nadir 2+ definition) and all patients had a minimum follow-up of 5 years. For contemporary patients from 2011, quality metrics from post-implant computed tomography as defined by RCR guidelines are presented. RESULTS: A mean D90 of 138.7 Gy (standard deviation 24.7) was achieved for the historic cohort. Biochemical control at 10 years was 76% in patients with D90 > 140 Gy and 68% in those with D90 < 140 Gy (P < 0.01). In current practice, over the last 3 years the mean (standard deviation) D90 has increased from 154 (15.3) Gy in 2011 to 164 (13.5) Gy in 2013. Similarly, an increase in the mean (standard deviation) V100 from 92 (4.4) to 95 (3.2) % is noted over time. No difference between clinicians was noted. CONCLUSION: D90 values of less than 140 Gy continue to be predictive of increased risk of recurrence of prostate cancer across risk groups with longer follow-up. Quality assurance can be used to ensure improved and consistent implant quality in a team with multiple clinicians.