"Why am I still suffering?": Experience of long-term fatigue and neurocognitive changes in oropharyngeal cancer survivors following (chemo)radiotherapy.

Background: Late effects of cancer treatment, such as neurocognitive deficits and fatigue, can be debilitating. Other than head and neck-specific functional deficits such as impairments in swallowing and speech, little is known about survivorship after oropharyngeal cancer. This study examines the lived experience of fatigue and neurocognitive deficits in survivors of oropharyngeal squamous cell cancer and impact on their daily lives. Methods: This work is part of the multicentre mixed method ROC-oN study (Radiotherapy for Oropharyngeal Cancer and impact on Neurocognition), evaluating fatigue and neurocognitive function in patients following radiotherapy +/- chemotherapy for oropharyngeal cancer and impact on quality of life. Semi-structured interviews were conducted in adults treated with radiotherapy (+/-chemotherapy) for oropharyngeal squamous cell carcinoma >/=24 months from completing treatment. Reflexive thematic analysis performed. Results: 21 interviews (11 men and 10 women; median age 58 years and median time post-treatment 5 years) were conducted and analysed, yielding six themes: (1) unexpected burden of fatigue, (2) noticing changes in neurocognitive function, (3) the new normal, (4) navigating changes, (5)insufficient awareness and (6)required support. Participants described fatigue that persisted beyond the acute post-treatment period and changes in neurocognitive abilities across several domains. Paid and unpaid work, emotions and mood were impacted. Participants described navigating the new normal by adopting self-management strategies and accepting external support. They reported lack of recognition of these late effects, being poorly informed and being unprepared. Follow-up services were thought to be inadequate. Conclusions: Fatigue and neurocognitive impairment were frequently experienced by survivors of oropharyngeal cancer, at least two years after treatment. Patients felt ill-prepared for these late sequelae, highlighting opportunities for improvement of patient information and support services.

Multi-institutional consensus on machine QA for isochronous cyclotron-based systems delivering ultra-high dose rate (FLASH) pencil beam scanning proton therapy in transmission mode.

BACKGROUND: The first clinical trials to assess the feasibility of FLASH radiotherapy in humans have started (FAST-01, FAST-02) and more trials are foreseen. To increase comparability between trials it is important to assure treatment quality and therefore establish a standard for machine quality assurance (QA). Currently, the AAPM TG-224 report is considered as the standard on machine QA for proton therapy, however, it was not intended to be used for ultra-high dose rate (UHDR) proton beams, which have gained interest due to the observation of the FLASH effect. PURPOSE: The aim of this study is to find consensus on practical guidelines on machine QA for UHDR proton beams in transmission mode in terms of which QA is required, how they should be done, which detectors are suitable for UHDR machine QA, and what tolerance limits should be applied. METHODS: A risk assessment to determine the gaps in the current standard for machine QA was performed by an international group of medical physicists. Based on that, practical guidelines on how to perform machine QA for UHDR proton beams were proposed. RESULTS: The risk assessment clearly identified the need for additional guidance on temporal dosimetry, addressing dose rate (constancy), dose spillage, and scanning speed. In addition, several minor changes from AAPM TG-224 were identified; define required dose rate levels, the use of clinically relevant dose levels, and the use of adapted beam settings to minimize activation of detector and phantom materials or to avoid saturation effects of specific detectors. The final report was created based on discussions and consensus. CONCLUSIONS: Consensus was reached on what QA is required for UHDR scanning proton beams in transmission mode for isochronous cyclotron-based systems and how they should be performed. However, the group discussions also showed that there is a lack of high temporal resolution detectors and sufficient QA data to set appropriate limits for some of the proposed QA procedures.

Neurocognitive function following (chemo)radiotherapy for nasopharyngeal cancer and other head and neck cancers: A systematic review.

When radiotherapy is used in the treatment of head and neck cancers, the brain commonly receives incidental doses of radiotherapy with potential for neurocognitive changes and subsequent impact on quality of life. This has not been widely investigated to date. A systematic search of MEDLINE, EMBASE, Psycinfo Info and the Cochrane Central Register of Controlled Trials (CENTRAL) electronic databases was conducted. Of 2077 records screened, 20 were eligible comprising 1308 patients. There were no randomised studies and 73.3% of included patients were from single center studies. IMRT was delivered in 72.6% of patients, and chemotherapy used in 61%. There was considerable heterogeneity in methods. Narrative synthesis was therefore carried out. Most studies demonstrated inferior neurocognitive outcomes when compared to control groups at 12 months and beyond radiotherapy. Commonly affected neurocognitive domains were memory and language which appeared related to radiation dose to hippocampus, temporal lobe, and cerebellum. Magnetic Resonance Imaging could be valuable in the detection of early microstructural and functional changes, which could be indicative of future neurocognitive changes. In studies investigating quality of life, the presence of neurocognitive impairment was associated with inferior quality of life outcomes. (Chemo)radiotherapy for head and neck cancer appears to be associated with a risk of long-term neurocognitive impairment. Few studies were identified, with substantial variation in methodology, thus limiting conclusions. High quality large prospective head and neck cancer studies using standardised, sensitive, and reliable neurocognitive tests are needed.

TORPEdO: A phase III trial of intensity-modulated proton beam therapy versus intensity-modulated radiotherapy for multi-toxicity reduction in oropharyngeal cancer.

•There is a lack of prospective level I evidence for the use of PBT for most adult cancers including oropharyngeal squamous cell carcinoma (OPSCC).•TORPEdO is the UK's first PBT clinical trial and aims to determine the benefits of PBT for OPSCC.•Training and support has been provided before and during the trial to reduce variations of contouring and radiotherapy planning.•There is a strong translational component within TORPEdO. Imaging and physics data along with blood, tissue collection will inform future studies in refining patient selection for IMPT.

Treatment planning considerations for the development of FLASH proton therapy.

With increasing focus on the translation of the observed FLASH effect into clinical practice, this paper presents treatment planning considerations for its development using proton therapy. Potential requirements to induce a FLASH effect are discussed along with the properties of existing proton therapy delivery systems and the changes in planning and delivery approaches required to satisfy these prerequisites. For the exploration of treatment planning approaches for FLASH, developments in treatment planning systems are needed. Flexibility in adapting to new information will be important in such an evolving area. Variations in definitions, threshold values and assumptions can make it difficult to compare different published studies and to interpret previous studies in the context of new information. Together with the fact that much is left to be understood about the underlying mechanism behind the FLASH effect, a systematic and comprehensive approach to information storage is encouraged. Collecting and retaining more detailed information on planned and realised dose delivery as well as reporting the assumptions made in planning studies creates the potential for research to be revisited and re-evaluated in the light of future improvements in understanding. Forward thinking at the time of study development can help facilitate retrospective analysis. This, we hope, will increase the available evidence and accelerate the translation of the FLASH effect into clinical benefit.

Improving workflow for adaptive proton therapy with predictive anatomical modelling: A proof of concept.

PURPOSE: To demonstrate predictive anatomical modelling for improving the clinical workflow of adaptive intensity-modulated proton therapy (IMPT) for head and neck cancer. METHODS: 10 radiotherapy patients with nasopharyngeal cancer were included in this retrospective study. Each patient had a planning CT, weekly verification CTs during radiotherapy and predicted weekly CTs from our anatomical model. Predicted CTs were used to create predicted adaptive plans in advance with the aim of maintaining clinically acceptable dosimetry. Adaption was triggered when the increase in mean dose (Dmean) to the parotid glands exceeded 3 Gy(RBE). We compared the accumulated dose of two adaptive IMPT strategies: 1) Predicted plan adaption: One adaptive plan per patient was optimised on a predicted CT triggered by replan criteria. 2) Standard replan: One adaptive plan was created reactively in response to the triggering weekly CT. RESULTS: Statistical analysis demonstrates that the accumulated dose differences between two adaptive strategies are not significant (p > 0.05) for CTVs and OARs. We observed no meaningful differences in D95 between the accumulated dose and the planned dose for the CTVs, with mean differences to the high-risk CTV of -1.20 %, -1.23 % and -1.25 % for no adaption, standard and predicted plan adaption, respectively. The accumulated parotid Dmean using predicted plan adaption is within 3 Gy(RBE) of the planned dose and 0.31 Gy(RBE) lower than the standard replan approach on average. CONCLUSION: Prediction-based replanning could potentially enable adaptive therapy to be delivered without treatment gaps or sub-optimal fractions, as can occur during a standard replanning strategy, though the benefit of using predicted plan adaption over the standard replan was not shown to be statistically significant with respect to accumulated dose in this study. Nonetheless, a predictive replan approach can offer advantages in improving clinical workflow efficiency.

Estimating the percentage of patients who might benefit from proton beam therapy instead of X-ray radiotherapy.

OBJECTIVES: High-energy Proton Beam Therapy (PBT) commenced in England in 2018 and NHS England commissions PBT for 1.5% of patients receiving radical radiotherapy. We sought expert opinion on the level of provision. METHODS: Invitations were sent to 41 colleagues working in PBT, most at one UK centre, to contribute by completing a spreadsheet. 39 responded: 23 (59%) completed the spreadsheet; 16 (41%) declined, arguing that clinical outcome data are lacking, but joined six additional site-specialist oncologists for two consensus meetings. The spreadsheet was pre-populated with incidence data from Cancer Research UK and radiotherapy use data from the National Cancer Registration and Analysis Service. 'Mechanisms of Benefit' of reduced growth impairment, reduced toxicity, dose escalation and reduced second cancer risk were examined. RESULTS: The most reliable figure for percentage of radical radiotherapy patients likely to benefit from PBT was that agreed by 95% of the 23 respondents at 4.3%, slightly larger than current provision. The median was 15% (range 4-92%) and consensus median 13%. The biggest estimated potential benefit was from reducing toxicity, median benefit to 15% (range 4-92%), followed by dose escalation median 3% (range 0 to 47%); consensus values were 12 and 3%. Reduced growth impairment and reduced second cancer risk were calculated to benefit 0.5% and 0.1%. CONCLUSIONS: The most secure estimate of percentage benefit was 4.3% but insufficient clinical outcome data exist for confident estimates. The study supports the NHS approach of using the evidence base and developing it through randomised trials, non-randomised studies and outcomes tracking. ADVANCES IN KNOWLEDGE: Less is known about the percentage of patients who may benefit from PBT than is generally acknowledged. Expert opinion varies widely. Insufficient clinical outcome data exist to provide robust estimates. Considerable further work is needed to address this, including international collaboration; much is already underway but will take time to provide mature data.

How do cognitive and functional impairment relate to the use of anticholinergic medications in hospitalised patients aged 65 years and over?

BACKGROUND: Anticholinergic medications are commonly prescribed to older adults despite their unfavourable pharmacological profile. There are no specific systems in place to alert prescribers about the wide range of medications with anticholinergic properties and their cumulative potential. AIMS: To examine associations between medications with anticholinergic properties and cognitive and functional impairment in hospitalised patients aged 65 years and older. METHODS: This descriptive, cross-sectional study included 94 patients admitted to a rehabilitation ward and a geriatric evaluation and management unit. Anticholinergic burden was calculated using the Anticholinergic Risk Scale. The Addenbrooke's Cognitive Examination and the Elderly Symptom Assessment Scale tools were utilised to assess cognitive function and burden of anticholinergic symptoms, respectively. RESULTS: Medications with anticholinergic properties were taken by 72.3% of patients with level 1 being the most commonly consumed (median 1, IQR = 0-2) medications. There was no association between anticholinergic medication use and cognitive function or anticholinergic symptoms. Increasing age and the hospital length of stay were associated with fewer anticholinergic symptoms (p < 0.001 and p = 0.021, respectively), whereas the total number of medications consumed was linked to a greater burden of anticholinergic symptoms (p < 0.001). CONCLUSION: A lack of association between anticholinergic medications and cognitive function could be related to duration of exposure to this group of medications and the age sensitivity. Additionally, the total number of medications consumed by patients was linked to a greater burden of anticholinergic symptoms. These findings highlight the need for improved knowledge and attentiveness when prescribing medications in general in this vulnerable population.

Inter-fraction robustness of intensity-modulated proton therapy in the post-operative treatment of oropharyngeal and oral cavity squamous cell carcinomas.

OBJECTIVE: To evaluate dosimetric consequences of inter-fraction setup variation and anatomical changes in patients receiving multifield optimised (MFO) intensity modulated proton therapy for post-operative oropharyngeal (OPC) and oral cavity (OCC) cancers. METHODS: Six patients receiving MFO for post-operative OPC and OCC were evaluated. Plans were robustly optimised to clinical target volumes (CTVs) using 3 mm setup and 3.5% range uncertainty. Weekly online cone beam CT (CBCT) were performed. Planning CT was deformed to the CBCT to create virtual CTs (vCTs) on which the planned dose was recalculated. vCT plan robustness was evaluated using a setup uncertainty of 1.5 mm and range uncertainty of 3.5%. Target coverage, D95%, and hotspots, D0.03cc, were evaluated for each uncertainty along with the vCT-calculated nominal plan. Mean dose to organs at risk (OARs) for the vCT-calculated nominal plan and relative % change in weight from baseline were evaluated. RESULTS: Robustly optimised plans in post-operative OPC and OCC patients are robust against inter-fraction setup variations and range uncertainty. D0.03cc in the vCT-calculated nominal plans were clinically acceptable across all plans. Across all patients D95% in the vCT-calculated nominal treatment plan was at least 100% of the prescribed dose. No patients lost ≥10% weight from baseline. Mean dose to the OARs and max dose to the spinal cord remained within tolerance. CONCLUSION: MFO plans in post-operative OPC and OCC patients are robust to inter-fraction uncertainties in setup and range when evaluated over multiple CT scans without compromising OAR mean dose. ADVANCES IN KNOWLEDGE: This is the first paper to evaluate inter-fraction MFO plan robustness in post-operative head and neck treatment.

Proton beam therapy: perspectives on the National Health Service England clinical service and research programme.

The UK has an important role in the evaluation of proton beam therapy (PBT) and takes its place on the world stage with the opening of the first National Health Service (NHS) PBT centre in Manchester in 2018, and the second in London coming in 2020. Systematic evaluation of the role of PBT is a key objective. By September 2019, 108 patients had started treatment, 60 paediatric, 19 teenagers and young adults and 29 adults. Obtaining robust outcome data is vital, if we are to understand the strengths and weaknesses of current treatment approaches. This is important in demonstrating when PBT will provide an advantage and when it will not, and in quantifying the magnitude of benefit.The UK also has an important part to play in translational PBT research, and building a research capability has always been the vision. We are perfectly placed to perform translational pre-clinical biological and physical experiments in the dedicated research room in Manchester. The nature of DNA damage from proton irradiation is considerably different from X-rays and this needs to be more fully explored. A better understanding is needed of the relative biological effectiveness (RBE) of protons, especially at the end of the Bragg peak, and of the effects on tumour and normal tissue of PBT combined with conventional chemotherapy, targeted drugs and immunomodulatory agents. These experiments can be enhanced by deterministic mathematical models of the molecular and cellular processes of DNA damage response. The fashion of ultra-high dose rate FLASH irradiation also needs to be explored.

The prognostic implication of perioperative cardiac enzyme elevation in patients with fractured neck of femur: A systematic review and meta-analysis.

BACKGROUND: Neck of Femur (NOF) fractures are a common injury in comorbid elderly patients which are associated with increased rates of morbidity and mortality following fracture. Because of their injury, patients can experience reductions in quality of life and independent living leading to transfer to nursing home or dependent levels of care. Numerous factors are associated with either complications or reductions in survival following fractured NOF. From the VISION cohort there is evidence that troponin elevation in the post-operative period following a diverse range of non-cardiac surgical procedures may lead to an increased risk of mortality in the absence of classical ischaemic or cardiac symptoms. The aim of this systematic review and meta-analysis is to validate the utility of perioperative troponin elevation as a prognostic indicator for mortality and cardiac morbidity in those with fractured NOF. METHODS: The PRISMA guidelines for the conduct of meta-analyses were followed. An electronic search was conducted of the EMBASE, MEDLINE (Ovid) and Biosis databases. Studies were included for analysis if they stratified outcomes by perioperative troponin elevation in surgically managed fractured NOF and reported sufficient data on troponin elevation and mortality following surgery. Primary and secondary outcomes assessed were all-cause post-operative mortality and a composite measure of cardiac complications (myocardial infarction, cardiac failure and arrhythmia) respectively. RESULTS: Eleven studies met inclusion criteria giving a total of 1363 patients. Overall, 497 patients (36.5%) experienced an elevation in troponin levels following surgery. Perioperative troponin elevation was significantly associated with all-cause mortality (OR 2.6; 95% CI 1.5 - 4.6; p <0.001) and cardiac complications (OR 7.4; 95% CI 3.5 - 15.8; p <0.001). Patient factors significantly associated with troponin elevation included pre-existing coronary artery disease, cardiac failure, hypertension, previous stroke and previous myocardial infarction. CONCLUSION: Perioperative troponin elevation is significantly associated with increased mortality and post-operative cardiac complications following fractured NOF and may be a useful prognostic indicator in these patients. Future research should further stratify patients by the magnitude of troponin elevation and further refine the risk factors.

An introduction to proton beam therapy.

Radiotherapy is a highly effective anti-cancer treatment commonly used alongside systemic therapies and surgery to achieve long-term cancer-free survival. Conventional radiotherapy uses photon beams to deliver a high dose of radiation to the tumour volume to eradicate cancer cells. This has to be offset against the irradiation of surrounding normal tissues, as increasing this dose causes more treatment-related toxicity. In August 2018, the NHS's first high energy proton beam therapy centre opened at The Christie NHS Foundation Trust in Manchester. A second NHS centre is scheduled to open in 2020 at the University College London Hospitals NHS Trust. Proton beam therapy may offer dosimetric advantages compared to conventional radiotherapy as a result of its characteristic dose deposition - proton beams deliver a comparatively higher proportion of their dose to the target volume relative to normal tissues, without significant exit doses when compared to conventional photon therapy. Therefore proton beam therapy may be indicated for certain tumours situated next to critical organs or in the paediatric population where quality of life and the reduction of secondary effects from radiation are particularly significant. The indications for proton beam therapy and patient outcomes after treatment will be carefully monitored and evaluated in order to provide a robust evidence base for its use.

Expansion of Luminal Progenitor Cells in the Aging Mouse and Human Prostate.

Aging is associated with loss of tissue mass and a decline in adult stem cell function in many tissues. In contrast, aging in the prostate is associated with growth-related diseases including benign prostatic hyperplasia (BPH). Surprisingly, the effects of aging on prostate epithelial cells have not been established. Here we find that organoid-forming progenitor activity of mouse prostate basal and luminal cells is maintained with age. This is caused by an age-related expansion of progenitor-like luminal cells that share features with human prostate luminal progenitor cells. The increase in luminal progenitor cells may contribute to greater risk for growth-related disease in the aging prostate. Importantly, we demonstrate expansion of human luminal progenitor cells in BPH. In summary, we define a Trop2+ luminal progenitor subset and identify an age-related shift in the luminal compartment of the mouse and human prostate epithelium.

Cry2 Is Critical for Circadian Regulation of Myogenic Differentiation by Bclaf1-Mediated mRNA Stabilization of Cyclin D1 and Tmem176b.

Circadian rhythms regulate cell proliferation and differentiation; however, little is known about their roles in myogenic differentiation. Our synchronized differentiation studies demonstrate that myoblast proliferation and subsequent myotube formation by cell fusion occur in circadian manners. We found that one of the core regulators of circadian rhythms, Cry2, but not Cry1, is critical for the circadian patterns of these two critical steps in myogenic differentiation. This is achieved through the specific interaction between Cry2 and Bclaf1, which stabilizes mRNAs encoding cyclin D1, a G1/S phase transition regulator, and Tmem176b, a transmembrane regulator for myogenic cell fusion. Myoblasts lacking Cry2 display premature cell cycle exit and form short myotubes because of inefficient cell fusion. Consistently, muscle regeneration is impaired in Cry2-/- mice. Bclaf1 knockdown recapitulated the phenotypes of Cry2 knockdown: early cell cycle exit and inefficient cell fusion. This study uncovers a post-transcriptional regulation of myogenic differentiation by circadian rhythms.

A robust optimisation approach accounting for the effect of fractionation on setup uncertainties.

Proton plans are subject to a number of uncertainties which must be accounted for to ensure that they are delivered safely. Misalignment resulting from residual errors in daily patient positioning can result in both a displacement and distortion of dose distributions. This can be particularly important for intensity modulated proton therapy treatments where the accurate alignment of highly modulated fields may be required to deliver the intended treatment. A number of methods to generate plans that are robust to these uncertainties exist. These include robust optimisation approaches which account for the effect of uncertainties on the dose distribution within the optimisation process. However, robustness to uncertainty comes at the cost of plan quality. For this reason, it is important that the uncertainties considered are realistic. Existing approaches to robust optimisation have neglected the role of fractionated treatment deliveries in reducing the uncertainties that result from random setup errors. Here, a method of robust optimisation which accounts for this effect is presented and is evaluated using a 2D planning environment. The optimisation algorithm considers the dose in the estimated upper and lower bounds of the dose distribution under the effect of setup and range errors. A comparison with plans robustly optimised without consideration of the effect of fractionation and conventionally optimised plans is presented. Fractionation incorporated robust optimisation demonstrates a reduced sensitivity to uncertainty compared to conventionally optimised plans and a reduced integral dose compared to robustly optimised plans.

Evaluation of Robustness to Setup and Range Uncertainties for Head and Neck Patients Treated With Pencil Beam Scanning Proton Therapy.

PURPOSE: To evaluate the robustness of head and neck plans for treatment with intensity modulated proton therapy to range and setup errors, and to establish robustness parameters for the planning of future head and neck treatments. METHODS AND MATERIALS: Ten patients previously treated were evaluated in terms of robustness to range and setup errors. Error bar dose distributions were generated for each plan, from which several metrics were extracted and used to define a robustness database of acceptable parameters over all analyzed plans. The patients were treated in sequentially delivered series, and plans were evaluated for both the first series and for the combined error over the whole treatment. To demonstrate the application of such a database in the head and neck, for 1 patient, an alternative treatment plan was generated using a simultaneous integrated boost (SIB) approach and plans of differing numbers of fields. RESULTS: The robustness database for the treatment of head and neck patients is presented. In an example case, comparison of single and multiple field plans against the database show clear improvements in robustness by using multiple fields. A comparison of sequentially delivered series and an SIB approach for this patient show both to be of comparable robustness, although the SIB approach shows a slightly greater sensitivity to uncertainties. CONCLUSIONS: A robustness database was created for the treatment of head and neck patients with intensity modulated proton therapy based on previous clinical experience. This will allow the identification of future plans that may benefit from alternative planning approaches to improve robustness.

Incorporating the effect of fractionation in the evaluation of proton plan robustness to setup errors.

To ensure the safe delivery of proton therapy treatments it is important to evaluate the effect of potential uncertainties, such as patient mispositioning, on the intended dose distribution. However, it can be expected that the uncertainty resulting from patient positioning is reduced in a fractionated treatment due to the convergence of random variables with the delivery of repeated treatments. This is neglected by current approaches to robustness analysis resulting in an overly conservative assessment of the robustness which can lead to sub-optimal plans. Here, a fast method of accounting for this reduced uncertainty is presented. An estimated bound to the error in the dose distribution resulting from setup uncertainty over a specified number of fractions is calculated by considering the distribution of values for each voxel across 14 initial error scenarios. The bound on the error in a given voxel is estimated using a 99.9% confidence limit assuming a convergence towards a normal distribution in line with the central limit theorem, and a correction of [Formula: see text] accounting for the reduction in the standard deviation over n fractions. The proposed method was validated in 5 patients by comparison to Monte Carlo simulations of 300 treatment courses. A voxelwise and volumetric analysis of the estimated and simulated bounds to the uncertainty in the dose distribution demonstrate that the proposed technique can be used to assess proton plan robustness more accurately allowing for less conservative treatment plans.

AutoLock: a semiautomated system for radiotherapy treatment plan quality control.

A semiautomated system for radiotherapy treatment plan quality control (QC), named AutoLock, is presented. AutoLock is designed to augment treatment plan QC by automatically checking aspects of treatment plans that are well suited to computational evaluation, whilst summarizing more subjective aspects in the form of a checklist. The treatment plan must pass all automated checks and all checklist items must be acknowledged by the planner as correct before the plan is finalized. Thus AutoLock uniquely integrates automated treatment plan QC, an electronic checklist, and plan finalization. In addition to reducing the potential for the propagation of errors, the integration of AutoLock into the plan finalization workflow has improved efficiency at our center. Detailed audit data are presented, demonstrating that the treatment plan QC rejection rate fell by around a third following the clinical introduction of AutoLock.