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Most cancer-related deaths are a result of metastasis, and thus the importance of this process as a target of therapy cannot be understated. By asking 'how can we effectively treat cancer?', we do not capture the complexity of a disease encompassing >200 different cancer types - many consisting of multiple subtypes - with considerable intratumoural heterogeneity, which can result in variable responses to a specific therapy. Moreover, we have much less information on the pathophysiological characteristics of metastases than is available for the primary tumour. Most disseminated tumour cells that arrive in distant tissues, surrounded by unfamiliar cells and a foreign microenvironment, are likely to die; however, those that survive can generate metastatic tumours with a markedly different biology from that of the primary tumour. To treat metastasis effectively, we must inhibit fundamental metastatic processes and develop specific preclinical and clinical strategies that do not rely on primary tumour responses. To address this crucial issue, Cancer Research UK and Cancer Therapeutics CRC Australia formed a Metastasis Working Group with representatives from not-for-profit, academic, government, industry and regulatory bodies in order to develop recommendations on how to tackle the challenges associated with treating (micro)metastatic disease. Herein, we describe the challenges identified as well as the proposed approaches for discovering and developing anticancer agents designed specifically to prevent or delay the metastatic outgrowth of cancer.

Objectives: This study investigates factors associated with use of real-world data (RWD) in economic modelling for single technology appraisals (STAs) of cancer drugs by the National Institute for Health and Care Excellence (NICE) to improve systematic understanding of the use of RWD., Methods: The data were extracted from STAs of cancer drugs, for which NICE issued guidance between January 2011 and December 2022 (n=267). Binary regression was used to test hypotheses concerning the greater or lesser use of RWD. Bonferroni-Holm correction was used to control error rates in multiple hypotheses tests. Several explanatory variables were considered in this analysis, including time (Time), incidence rate of disease (IR), availability of direct treatment comparison (AD), generalisability of trial data (GE), maturity of survival data in trial (MS) and previous technology recommendations by NICE (PR). The primary outcome variable was any use of RWD. Secondary outcome variables were specific uses of RWD in economic models., Results: AD had a statistical negative association with any use of RWD whereas no associations with non-parametric and parametric use of RWD were found. Time had several statistical associations with use of RWD (validating survival distributions for the intervention, estimating progression-free survival for the intervention, estimating overall survival for comparators and transition probabilities)., Conclusions: RWD were more likely to be used in economic modelling of cancer drugs when randomised controlled trials failed to provide relevant clinical information of the drug for appraisals, particularly in the absence of direct treatment comparisons. These results, based on analysis of data systematically collected from previous appraisals, suggest that uses of RWD were associated with data gaps in the economic modelling. While this result may support some of the claimed advantages of using RWD when evidence is absent, the question, the extent to which use of RWD in indirect treatment comparisons reduces uncertainty is still to be determined., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jiyeon Kang is supported by the Centre for Cancer Biomarkers, University of Bergen, funded by the Research Council of Norway grant number (223250). She also holds a ESRC (Economic and Social Research Council) postdoctoral fellowship. The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Also, any fellowship or external contribution had no impacts on this paper. John Cairns is a diagnostic advisory committee member of the National Institute for Health and Care Excellence., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This study summarises research- and practice-based evidence on home-based chemotherapy, and explores existing delivery models. A three-pronged investigation was conducted consisting of a literature review and synthesis of 54 papers, a review of seven home-based chemotherapy programmes spanning four countries, and two case studies within the Canadian province of Ontario. The results support the provision of home-based chemotherapy as a safe and patient-centred alternative to hospital- and outpatient-based service. This paper consolidates information on home-based chemotherapy programmes including services and drugs offered, patient eligibility criteria, patient views and experiences, delivery structures and processes, and common challenges. Fourteen recommendations are also provided for improving the delivery of chemotherapy in patients' homes by prioritising patient-centredness, provider training and teamwork, safety and quality of care, and programme management. The results of this study can be used to inform the development of an evidence-informed model for the delivery of chemotherapy and related care, such as symptom management, in patients' homes. [ABSTRACT FROM AUTHOR]

Deborah Robertson provides an overview of recently published articles that may be of interest to non-medical prescribers. Should you wish to look at any of the papers in more detail, a full reference is provided [ABSTRACT FROM AUTHOR]

Drawing on literature on values in science and a case-study of UK cancer policy, this paper argues for a novel account of the demarcation project in terms of trustworthiness. The first part of the paper addresses the relationship between science, politics and demarcation. In 2010, the UK government decided to pay more for cancer drugs than for drugs for other diseases; in 2016, this Cancer Drugs Fund was reformed so as to lower the evidential standards for approving cancer drugs, rather than paying more for them. Are these two ways of treating cancer as "special" importantly different? This paper argues that, if we the argument from inductive risk seriously, they seem equivalent. This result provides further reason to doubt the notion of demarcating science from non-science. However, the second part of the paper complicates this story, arguing that considerations of epistemic trust might give us reasons to prefer epistemic communities centred around "broadly acceptable" standards, and which are "sociologically well-ordered", regardless of inductive risk concerns. After developing these claims through the cancer case-study, the final section suggests how these concerns might motivate novel versions of the demarcation project. [ABSTRACT FROM AUTHOR]

The article focuses on the study which seeks to analyze possible remedies for cancer growth in Great Britain. It claims that montesanib diphosphate, an antigiogenic agent (AMG 706), has been evaluated as a potential treatment for progressive differentiated thyroid cancer (PDTC). On the other hand, CTC-chip has been employed in analyzing the isolated circulating tumor cells of epidermal growth factor receptor (EGFR) mutations.

Simple Summary: Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths in the United Kingdom. Advances in treatments such as chemotherapy, targeted therapies, and immunotherapies have significantly improved outcomes for patients. However, these treatments have raised concerns about their potential heart-related side effects. This study investigated this issue using the UK's Yellow Card System, which collects data on drug side effects. The study examined adverse event reports for 56 NSCLC drugs, finding 128,214 adverse events, of which 6133 were cardiovascular issues. Alectinib emerged as the drug with the highest reported risk of cardiovascular problems, aligning with findings from other databases like the WHO's VigiBase. Although alectinib has been shown to significantly improve the survival rate of cancer patients, continuous monitoring is essential to ensure a benefit–risk balance can be maintained. Background: Non-small cell lung cancer (NSCLC) is a predominant cause of oncological mortality in the United Kingdom. There is a diverse spectrum of therapeutic options available, such as chemotherapies, targeted therapies and immunotherapies, which have significantly advanced patient prognoses. However, despite these advancements, there is an escalating concern regarding the potential cardiotoxic effects associated with these treatments. Objectives: This study aimed to explore the association between non-small cell lung cancer treatments and cardiotoxicity. Methods: A pharmacovigilance study was conducted utilising the UK Yellow Card System. The proportional reporting ratio (PRR) and reporting odds ratio (ROR) were calculated to detect signals. Results: Among the 56 shortlisted NSCLC drugs, the total number of adverse events reported was 128,214 with 6133 reports being cardiovascular adverse reactions. Among all the drugs analysed, alectinib demonstrated the highest ROR and PRR values, indicating the strongest signal for potential cardiovascular adverse events. Conclusions: This result was comparable to previous studies which also detected a signal of alectinib related to cardiovascular events using the WHO pharmacovigilance database, VigiBase. However, clinical studies demonstrated that alectinib largely improved progression-free survival (PFS) and overall survival in patients. Therefore, it is important to continue monitoring the real-world use of alectinib, so that a benefit–risk balance can be maintained. [ABSTRACT FROM AUTHOR]

Objective We wished to explore how UK national newspapers had covered the creation and operation of the Cancer Drugs Fund from 2010 to 2015. This was introduced to provide cancer patients in England with access to drugs not appraised or approved by the National Institute for health and Care Excellence. Design We sought stories in nine newspapers from the Factiva database, and copied their salient details to a spreadsheet. They were categorised by whether they were supportive or critical of the Cancer Drugs Fund and their main arguments, which drugs they mentioned and for which cancers. Settings Not applicable Participants Not applicable Main outcome results Press coverage was mainly very positive, arguing for the Cancer Drugs Fund's extension to Scotland and Wales, and a bigger budget, but neglecting the lack of patient benefit and the severe side effects that sometimes occurred. Leading this support was the Daily Mail, whose influence (measured by the product of number of stories and the paper's circulation) was almost greater than that of the other newspapers combined. Results Press coverage was mainly very positive, arguing for the Cancer Drugs Fund's extension to Scotland and Wales, and a bigger budget, but neglecting the lack of patient benefits and the severe side effects that sometimes occurred. Leading this support was the Daily Mail, whose influence (measured by the product of number of stories and the paper's circulation) was almost greater than that of the other newspapers combined. Conclusions Although there was some critical analysis of the Cancer Drugs Fund, our analysis shows that most press coverage was largely positive and unrepresentative in comparison with the lack of overall benefits to patients and society. It is likely that it contributed to the Cancer Drugs Fund's continuation despite mounting evidence of its ineffectiveness.

The National Institute for Health and Care Excellence (NICE), as part of the institute's single technology appraisal (STA) process, invited the company that makes obinutuzumab (Roche Products Limited) to submit evidence of the clinical and cost effectiveness of the drug in combination with chemotherapy, with or without obinutuzumab as maintenance therapy for adult patients with untreated, advanced follicular lymphoma (FL) in the UK. Kleijnen Systematic Reviews Ltd (KSR), in collaboration with Erasmus University Rotterdam, was commissioned to act as the Evidence Review Group (ERG). This paper describes the company's submission, the ERG review, and NICE's subsequent decisions. The clinical evidence was derived from two phase III, company-sponsored, randomised, open-label studies. Most evidence on obinutuzumab was based on the GALLIUM trial that compared obinutuzumab in combination with chemotherapy as induction followed by obinutuzumab maintenance monotherapy with rituximab in combination with chemotherapy as induction followed by rituximab maintenance monotherapy in previously untreated patients with FL (grades 1-3a). Long-term clinical evidence was based on the PRIMA trial, studying the benefit of two years of rituximab maintenance after first-line treatment in patients with FL. The cost-effectiveness evidence submitted by the company relied on a partitioned survival cost-utility model, implemented in Microsoft® Excel. The base-case incremental cost-effectiveness ratio (ICER) presented in the company submission was <£20,000 per quality-adjusted life-year (QALY) gained. Although the ERG concluded that the economic model met the NICE reference case to a reasonable extent, some errors were identified and several assumptions made by the company were challenged. A new base-case scenario produced by the ERG suggested an ICER that was higher than the company base case, but still below £30,000 per QALY gained. However, some ERG scenario analyses were close to or even above the threshold. This was the case in particular for assuming a treatment effect that did not extend beyond trial follow-up. These results led to an initial negative recommendation by the appraisal committee. Subsequently, the company submitted a revised base case focusing on patients at intermediate or high risk of premature mortality. Simultaneously, a further price discount for obinutuzumab was granted. In addition to the company's revised base case, the ERG suggested a restriction of the treatment effect to 5 years and implemented biosimilar uptake and cheaper prices for rituximab. All of these adjustments did not exceed £30,000 per QALY gained and therefore the use of obinutuzumab for patients with advanced FL and a Follicular Lymphoma International Predictive Index (FLIPI) score of two or more could be recommended. [ABSTRACT FROM AUTHOR]

Background: Rising cancer incidence, the cost of cancer pharmaceuticals and the introduction of the Cancer Drugs Fund in England, but not other United Kingdom(UK) countries means evidence of 'postcode prescribing' in cancer is important. There have been no systematic reviews considering access to cancer drugs by geographical characteristics in the UK.Methods: Studies describing receipt of cancer drugs, according to healthcare boundaries (e.g. cancer network [UK]) were identified through a systematic search of electronic databases and grey literature. Due to study heterogeneity a meta-analysis was not possible and a narrative synthesis was performed.Results: 8,780 unique studies were identified and twenty-six included following a systematic search last updated in 2015. The majority of papers demonstrated substantial variability in the likelihood of receiving chemotherapy between hospitals, health authorities, cancer networks and UK countries (England and Wales). After case-mix adjustment, there was up to a 4-5 fold difference in chemotherapy utilisation between the highest and lowest prescribing cancer networks. There was no strong evidence that rurality or distance travelled were associated with the likelihood of receiving chemotherapy and conflicting evidence for an effect of travel time.Conclusions: Considerable variation in chemotherapy prescribing between healthcare boundaries has been identified. The absence of associations with natural geographical characteristics (e.g. rurality) and receipt of chemotherapy suggests that local treatment habits, capacity and policy are more influential. [ABSTRACT FROM AUTHOR]

The allocation of funding for new anticancer treatments within the UK has not kept pace with demand. Clinicians find themselves restricted in the use of licensed drugs which they feel are in the best interests of individual patients. Against this, health authorities have a duty to ensure that scarce resources are used equitably to meet the needs of the local population as a whole. Differential levels of funding for new treatments across the country have led to concerns about rationing by postcode. This paper outlines an approach to the prioritization of new treatment for advanced cancer developed jointly by clinicians and health authorities in South London. The approach involves evidence reviews and consensus meetings. Existing and new treatments are rated on a four-point 'relative effectiveness scale', which takes account of the impact of the treatment on quality of life and on survival. The strength of evidence supporting each effectiveness rating is also classified. Health Authorities have used these ratings to determine overall funding levels, while leaving decisions on individual patients to the relevant Trusts. [ABSTRACT FROM AUTHOR]

The cellular response to cisplatin was assessed in human osteosarcoma cells, using synchrotron-based (SR) Fourier Transform InfraRed nanospectroscopy (nano-FTIR) at the MIRIAM beamline B22 of Diamond Light Source (UK). This label-free mapping method delivered simultaneous morphological and biochemical information on a subcellular level (i.e. 100 s nanometer or better). Based on specific spectral biomarkers, the main biochemical constituents affected by the drug were identified at distinct locations within the cell´s inner body. Cisplatin was shown to have a noteworthy effect on proteins, mostly within the cytoplasm. A clear drug impact on cellular lipids was also observed. Within current literature on s-SNOM, this nanospectroscopy work represents a first successful application in life sciences providing full fingerprint nano-FTIR spectra across intact human cancer cells. [ABSTRACT FROM AUTHOR]

Background: The present report was commissioned as a supplement to an existing technology assessment report produced by the Peninsula Technology Assessment Group (PenTAG), which evaluated the clinical effectiveness and cost-effectiveness of dasatinib and nilotinib in patients who are either resistant or intolerant to standard-dose imatinib., Objectives: This report evaluates the clinical effectiveness and cost-effectiveness of dasatinib, nilotinib and high-dose imatinib within their licensed indications for the treatment of people with chronic myeloid leukaemia (CML) who are resistant to standard-dose imatinib., Data Sources: Bibliographic databases were searched from inception to January 2011, including The Cochrane Library, MEDLINE (Ovid), EMBASE (Ovid), and MEDLINE In-Process & Other Non-Indexed Citations. Bibliographies of related papers were screened, key conferences were searched, and experts were contacted to identify additional published and unpublished references., Review Methods: This report includes systematic reviews of clinical effectiveness and cost-effectiveness studies, an independent appraisal of information submitted by drug manufacturers to the National Institute for Health and Clinical Excellence (NICE), an independent appraisal of the PenTAG economic evaluation, and new economic analyses adapting the PenTAG economic model. Standard systematic procedures involving two reviewers to maintain impartiality and transparency, and to minimise bias, were conducted., Results: Eleven studies met the inclusion criteria. Four of these studies included new data published since the PenTAG report; all of these were in chronic-phase CML. No relevant studies on the clinical effectiveness of nilotinib were found. The clinical effectiveness studies on dasatinib [one arm of a randomised controlled trial (RCT)] and high-dose imatinib (one arm of a RCT and three single-arm cohort studies) had major methodological limitations. These limitations precluded a comparison of the different arms within the RCT. Data from the studies are summarised in this report, but caution in interpretation is required. One economic evaluation was identified that compared dasatinib with high-dose imatinib in patients with chronic-phase CML who were CML resistant to standard-dose imatinib. Two industry submissions and the PenTAG economic evaluation were critiqued and differences in the assumptions and results were identified. The PenTAG economic model was adapted and new analyses conducted for the interventions dasatinib, nilotinib and high-dose imatinib and the comparators interferon alfa, standard-dose imatinib, stem cell transplantation and hydroxycarbamide. The results suggest that the three interventions, dasatinib, nilotinib and high-dose imatinib, have similar costs and cost-effectiveness compared with hydroxycarbamide, with a cost-effectiveness of around £30,000 per quality-adjusted life-year gained. However, it is not possible to derive firm conclusions about the relative cost-effectiveness of the three interventions owing to great uncertainty around data inputs. Uncertainty was explored using deterministic sensitivity analyses, threshold analyses and probabilistic sensitivity analyses., Limitations: The paucity of good-quality evidence should be considered when interpreting this report., Conclusions: This review has identified very limited new information on clinical effectiveness of the interventions over that already shown in the PenTAG report. Limitations in the data exist; however, the results of single-arm studies suggest that the interventions can lead to improvements in haematological and cytogenetic responses in people with imatinib-resistant CML. The economic analyses do not highlight any one of the interventions as being the most cost-effective; however, the analysis results are highly uncertain owing to lack of agreement on appropriate assumptions. Recommendations for future research made by PenTAG, for a good-quality RCT comparing the three treatments remain.

Background: A gap analysis was conducted to determine which areas of breast cancer research, if targeted by researchers and funding bodies, could produce the greatest impact on patients., Methods: Fifty-six Breast Cancer Campaign grant holders and prominent UK breast cancer researchers participated in a gap analysis of current breast cancer research. Before, during and following the meeting, groups in seven key research areas participated in cycles of presentation, literature review and discussion. Summary papers were prepared by each group and collated into this position paper highlighting the research gaps, with recommendations for action., Results: Gaps were identified in all seven themes. General barriers to progress were lack of financial and practical resources, and poor collaboration between disciplines. Critical gaps in each theme included: (1) genetics (knowledge of genetic changes, their effects and interactions); (2) initiation of breast cancer (how developmental signalling pathways cause ductal elongation and branching at the cellular level and influence stem cell dynamics, and how their disruption initiates tumour formation); (3) progression of breast cancer (deciphering the intracellular and extracellular regulators of early progression, tumour growth, angiogenesis and metastasis); (4) therapies and targets (understanding who develops advanced disease); (5) disease markers (incorporating intelligent trial design into all studies to ensure new treatments are tested in patient groups stratified using biomarkers); (6) prevention (strategies to prevent oestrogen-receptor negative tumours and the long-term effects of chemoprevention for oestrogen-receptor positive tumours); (7) psychosocial aspects of cancer (the use of appropriate psychosocial interventions, and the personal impact of all stages of the disease among patients from a range of ethnic and demographic backgrounds)., Conclusion: Through recommendations to address these gaps with future research, the long-term benefits to patients will include: better estimation of risk in families with breast cancer and strategies to reduce risk; better prediction of drug response and patient prognosis; improved tailoring of treatments to patient subgroups and development of new therapeutic approaches; earlier initiation of treatment; more effective use of resources for screening populations; and an enhanced experience for people with or at risk of breast cancer and their families. The challenge to funding bodies and researchers in all disciplines is to focus on these gaps and to drive advances in knowledge into improvements in patient care.

LOO S.W., GEROPANTAS K., TASIGIANNOPOULOS Z., MARTIN C. & ROQUES T.W. (2013) European Journal of Cancer Care 22, 32-40 Feasibility and tolerance of sequential chemoradiotherapy in squamous cell carcinoma of the head and neck This paper evaluates the feasibility and tolerance of sequential chemoradiotherapy in patients with squamous cell carcinoma of the head and neck and ascertains whether the use of induction chemotherapy compromises delivery of subsequent radiotherapy with or without concurrent chemotherapy. We also compared sequential chemoradiotherapy treatment adherence between the elderly and younger patients with squamous cell carcinoma of the head and neck. One hundred and ninety-four patients with head and neck squamous cell carcinoma who received induction chemotherapy with cisplatin and 5-fluorouracil were included in this study. Treatment-related death rate from induction chemotherapy was 1.5%. One hundred and ninety-one patients (98.5%) proceeded to radical radiotherapy, with 90.1% also receiving planned concomitant chemotherapy. One hundred and seventy-eight patients (93.2%) completed radiotherapy with no prolongation of the treatment duration. There were no statistical differences in sequential chemoradiotherapy treatment adherence and tolerance between the elderly and younger patients apart from the proportion who required hospitalisation during radiotherapy. Induction chemotherapy in head and neck squamous cell carcinoma does not compromise delivery of definitive radiotherapy with or without concurrent chemotherapy. Elderly patients with head and neck squamous cell carcinoma are able to tolerate aggressive treatments such as sequential chemoradiotherapy. Treatment 'deintensification' based solely on chronological age is not recommended. [ABSTRACT FROM AUTHOR]

Featured Application: This opinion piece discusses the limitations of the current cytotoxic dosing methods and how advanced body measurement techniques could be used by oncology practitioners to determine cytotoxic chemotherapy dosages for patients, regardless of their body size. Within chemotherapy, estimates of a patient's body surface area (BSA) are used to calculate drug dosages. However, the use of BSA for calculating chemotherapy dosage has been heavily criticised in previous literature, with potentially significant implications for the effectiveness and toxicity of treatment. BSA has been found to be a poor indicator of optimal drug exposure that does not account for the complex processes of cytotoxic drug distribution and elimination. In addition, differences in BSA estimates between existing formulae have been shown to be so large that they can affect patients' mortality, particularly in patients with atypical body types. This uncertainty associated with BSA prediction may decrease the confidence of practitioners when determining chemotherapy dosages, particularly with regards to the risk of excess toxicity from over-dosing, or a reduced anti-cancer effect due to under-dosing. The use of national dose-banding in the UK may in some cases account for possible inaccuracies, but the threshold of variance in this case is small (+/−6%). Advanced body measurement techniques, utilising digital tools such as three-dimensional (3D) surface imaging, capture accurate external dimensions and detailed shape characteristics of the human body. Measures of body shape describe morphological variations that cannot be identified by traditional anthropometric techniques and improve the prediction of total body fat and distribution. It is our view that the use of advanced body measurement techniques can provide practitioners with tools for prescribing chemotherapy dosages that are valid for individuals, regardless of their body type. [ABSTRACT FROM AUTHOR]

This is the first of two articles on C1 inhibitor deficiency based on a recent UK consensus document covering diagnosis and management of the disorder in both adults and children. This paper focuses on diagnosis of this disorder. [ABSTRACT FROM AUTHOR]

Medication adherence to hormone therapy (HT) in breast cancer survivors is often suboptimal and is affected by a range of factors. Patients are usually prescribed different generic formulations of HT drugs and their impact on side effects and on adherence and persistence is poorly understood. This study aimed to explore women's lived experience of HT medication brand changes (generic substitution) and its impact on side effects, quality of life and medication-taking behaviors, as well as on adherence and persistence. Nine female breast cancer survivors who had previous experience of HT medication brand changes participated in the study. Individual, online, semi-structured interviews were conducted and analyzed using interpretative phenomenological analysis. The findings identified three superordinate themes and nine subordinate themes that influenced the lived experience of medication brand changes for these patients: (i) experiencing brand changes, (ii) responsiveness of health care providers and (iii) future expectations. Women reported negative physical and emotional experiences of brand changes, which is often compounded by healthcare professionals' lack of information and reassurances, disbelief in the worsening of side effects and inconsistent advice regarding generics. These have implications for women's self-efficacy for medication-taking behaviors, ability to manage side effects and HT adherence and persistence. [ABSTRACT FROM AUTHOR]

Purpose: Chemoradiation therapy (CRT) for patients with locally advanced pancreatic cancer (LAPC) provides survival benefits but may result in considerable toxicity. Health-related quality of life (HRQL) measurements during CRT have not been widely reported. This paper reports HRQL data from the Selective Chemoradiation in Advanced Localised Pancreatic Cancer (SCALOP) trial, including validation of the QLQ-PAN26 tool in CRT.Methods and Materials: Patients with locally advanced, inoperable, nonmetastatic carcinoma of the pancreas were eligible. Following 12 weeks of induction gemcitabine plus capecitabine (GEMCAP) chemotherapy, patients with stable and responding disease were randomized to a further cycle of GEMCAP followed by capecitabine- or gemcitabine-based CRT. HRQL was assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and the EORTC Pancreatic Cancer module (PAN26).Results: A total of 114 patients from 28 UK centers were registered and 74 patients randomized. There was improvement in the majority of HRQL scales during induction chemotherapy. Patients with significant deterioration in fatigue, appetite loss, and gastrointestinal symptoms during CRT recovered within 3 weeks following CRT. Differences in changes in HRQL scores between trial arms rarely reached statistical significance; however, where they did, they favored capecitabine therapy. PAN26 scales had good internal consistency and were able to distinguish between subgroups of patients experiencing toxicity.Conclusions: Although there is deterioration in HRQL following CRT, this resolves within 3 weeks. HRQL data support the use of capecitabine- over gemcitabine-based chemoradiation. The QLQ-PAN26 is a reliable and valid tool for use in patients receiving CRT. [ABSTRACT FROM AUTHOR]

Background. Randomized studies of neoadjuvant (NA) trastuzumab and pertuzumab combined with chemotherapy for HER2-positive breast cancers (BC) have reported pathological complete response (pCR) rates of 39 to 61%. This study aimed to determine the real-world efficacy and toxicity of NA trastuzumab and pertuzumab combined with chemotherapy in a UK tertiary referral cancer centre. Methods. HER2-positive early BC patients given neoadjuvant chemotherapy with trastuzumab and pertuzumab between October 2016 and February 2018 at our tertiary referral cancer centre were identified via pharmacy records. Clinico-pathological information, treatment regimens, treatment-emergent toxicities, operative details, and pathological responses and outcomes were recorded. Results. 78 female patients were identified; 2 had bilateral diseases and 48 of 78 (62%) were node positive at presentation. 55 of 80 (71%) tumours were ER-positive. PCR occurred in 37 of 78 (46.3%; 95% CI: 35.3–57.2%) patients. 14 of 23 (60.8%) patients with ER-negative tumours achieved pCR; 23 of 55 (41.8%) were ER-positive and 6 of 19 (31.6%) were ER-positive and PgR-positive. No cardiac toxicity was documented. Diarrhoea occurred in 53 of 72 (74%) patients. Grade 3–4 toxicity occurred in ≥2% patients. These were diarrhoea, fatigue, and infection. The Median follow up period was 45.2 months (95% CI 43.8–46.3) with 71 of 78 (91.0%) remaining disease-free and 72 of 78 (92.3%) alive. Estimated OS at 2 years 86% (95% CI: 75–99%). Conclusion. This data confirms the efficacy of neoadjuvant chemotherapy combined with dual HER2 directed therapy. While no cardiac toxicity was observed, diarrhoea occurred frequently. The low pCR rate observed in ER and PgR-positive BCs warrants further investigation and consideration of strategies to increase the pCR rate. [ABSTRACT FROM AUTHOR]

Abstract: The SCOPE 1 trial closed to recruitment in early 2012 and has demonstrably improved the quality of UK radiotherapy. It has also shown that there is an enthusiastic upper gastrointestinal clinical oncology community that can successfully complete trials and deliver high-quality radiotherapy. Following on from SCOPE 1, this paper, authored by a consensus of leading UK upper gastrointestinal radiotherapy specialists, attempts to define current best practice and the questions to be answered by future clinical studies. The two main roles for chemoradiotherapy (CRT) in the management of potentially curable oesophageal cancer are definitive (dCRT) and neoadjuvant (naCRT). The rates of local failure after dCRT are consistently high, showing the need to evaluate more effective treatments, both in terms of optimal local and systemic therapeutic components. This will be the primary objective of the next planned UK dCRT trial and here we discuss the role of dose escalation and systemic therapeutic options that will form the basis of that trial. The publication of the Dutch ‘CROSS’ trial of naCRT has shown that this pre-operative approach can both be given safely and offer a significant survival benefit over surgery alone. This has led to the development of the UK NeoSCOPE trial, due to open in 2013. There will be a translational substudy to this trial and currently available data on the role of biomarkers in predicting response to therapy are discussed. Postoperative reporting of the pathology specimen is discussed, with recommendations for the NeoSCOPE trial. Both of these CRT approaches may benefit from recent developments, such as positron emission tomography/computed tomography and four-dimensional computed tomography for target volume delineation, planning techniques such as intensity-modulated radiotherapy and ‘type b’ algorithms and new treatment verification methods, such as cone-beam computed tomography. These are discussed here and recommendations made for their use. [Copyright &y& Elsevier]

As part of its Single Technology Appraisal (STA) process, the UK National Institute for Health and Care Excellence (NICE) invited the manufacturer (EUSA Pharma) of dinutuximab beta (Qarziba®) to submit evidence of its clinical and cost effectiveness for treating neuroblastoma. The BMJ Technology Assessment Group (BMJ-TAG) was commissioned to act as the Evidence Review Group (ERG), reviewing the submission from the company. The Decision Support Unit (DSU) was commissioned to review additional evidence submitted by the company and to undertake further analyses. This article presents the critical review of the company's submissions by the ERG and DSU, further analyses undertaken by the DSU, and the outcome of the NICE guidance. The clinical effectiveness for dinutuximab beta was derived from a phase III randomised controlled trial (RCT) that assessed the safety and efficacy of the addition of interleukin (IL)-2 to dinutuximab beta plus isotretinoin. This trial did not inform the relative effectiveness of dinutuximab beta versus isotretinoin alone, which was established practice in the UK for maintenance treatment. In the absence of direct evidence, the company initially conducted a naïve indirect treatment comparison against a historical control, and later performed a matching-adjusted indirect comparison (MAIC) against the isotretinoin arm of an RCT comparing dinutuximab alpha and isotretinoin. The company submitted a partitioned survival analysis model that calculated the incremental cost effectiveness of dinutuximab beta versus isotretinoin. The company's original incremental cost-effectiveness ratio (ICER) was £22,338 per quality-adjusted life-year (QALY) gained. However, the ERG were concerned that the company's ICER was not suitable for decision making, and thus carried out initial exploratory analysis as a first step to overcome the naïve estimation of treatment effectiveness in the model. The ERG's analysis estimated an ICER of £111,858 per QALY gained. In their revised analysis incorporating the MAIC and other changes as requested by the appraisal committee, the company's ICER was £24,661 per QALY gained. When the DSU incorporated longer-term isotretinoin data and made corrections to the model, the ICER increased to between £62,886 and £87,164 per QALY gained depending on the choice of survival model. A confidential Patient Access Scheme (PAS) decreased the ICERs. The ICERs with the PAS were over £40,000 per QALY gained, but the NICE committee additionally considered the patient population and its size, the disease severity, the potential for significant survival benefit and uncaptured health benefits, and recommended dinutuximab beta as a treatment option, subject to the company providing the agreed discount in the PAS. [ABSTRACT FROM AUTHOR]

The authors discuss the implications of the 2015 proposed revision of the Cancer Drugs Fund (CDF), established to provide a means by which National Health Service (NHS) patients could get cancer drugs that are not available on the NHS in Great Britain. They argues against the threats of the revised scheme on public health. They describe how the revised CDF could maximize the value of the benefit to cancer patients while minimizing its negative impact on the equity and efficiency of the NHS.

Objectives: The combination of 5-fluorouracil (5-FU), irinotecan and oxaliplatin (FOLFIRINOX) is considered the first-line chemotherapy for fit patients with advanced pancreatic ductal adenocarcinoma (PDAC) but carries an unfavourable adverse event (AE) profile. We retrospectively evaluated the tolerability and efficacy of a modified FOLFIRINOX (mFOLFIRINOX) regimen: intravenous oxaliplatin 85 mg/m2, irinotecan 135 mg/m2, folinic acid 400 mg/m2 and 5-FU infusion 2,400 mg/m2 over 46 h, with routine subcutaneous filgrastim on a 14-day cycle. Methods: Records of 18 patients with advanced PDAC who received treatment with mFOLFIRINOX were reviewed. Imaging of measurable disease was assessed for response, and survival was measured from the date of commencing chemotherapy to disease progression and/or death. Results: Grade 3 or 4 AEs (n; %) included vomiting (5; 28), nausea (4; 22), diarrhoea (3; 17) and non-neutropaenic fever (3; 17). For patients with stage IV disease, 12/15 (80%) achieved at least stable disease as the best radiological response, with 7/15 (47%) objective responses. In this subgroup, median overall and progression-free survival were 9.3 months (95% CI 8.3-10.4) and 7.2 months (95% CI 4.7-9.6), respectively. Conclusion: Compared to full-dose FOLFIRINOX, our modified regimen resulted in lower haematological but only marginally improved non-haematological toxicity rates, with comparable efficacy outcomes. Prospective studies are required to validate these findings. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background. Scientific advances have led to the discovery of novel treatments with high prices. The cost to publicly fund high-cost drugs may threaten the sustainability of drug budgets in different health care systems. In oncology, there are concerns that health-benefit gains are diminishing over time and that the economic evidence to support funding decisions is too limited. Methods. To assess the additional costs and benefits gained from oncology drugs over time, we used treatment protocols and efficacy results from U.S. Food and Drug Administration records to calculate cost-effectiveness ratios for drugs approved to treat first- and second-line metastatic or advanced breast, colorectal, and non-small cell lung cancer during the years 1994-2013. We assessed reimbursement recommendations reached by health technology assessment agencies in the U.K., Australia, and Canada. Results. Cost-effectiveness ratios were calculated for 50 drugs approved by the U.S. regulator. The more recent approvals were often based on surrogate efficacy outcomes and had extremely high costs, often triple the costs of drugs approved in previous years. Over time, the effectiveness gains have increased for some cancer indications; however, for other indications (non-small cell lung and second-line colorectal cancer), the magnitude of gains in effectiveness decreased. Reimbursement recommendations for drugs with the highest cost-effectiveness ratios were the most inconsistent. Conclusion. Evaluation of the clinical benefits that oncology drugs offer as a function of their cost has become highly complex, and for some clinical indications, health benefits are diminishing over time. There is an urgent need for better economic evidence from oncology drug trials and systematic processes to inform funding decisions. [ABSTRACT FROM AUTHOR]

Background Phase I trials of the microtubule stabilising agent patupilone showed encouraging tumour control and response rates in patients with metastatic colorectal cancer. Methods Patients with metastatic or locally recurrent colorectal cancer who had progressed following treatment with oxaliplatin, irinotecan and fluoropyrimidines were treated with patupilone (8 mg/m IV every 3 weeks) in combination with dexamethasone or prednisolone. Results The trial was closed early after 29 patients had been enrolled due to concerns about toxicity. 20 patients (71.4 %) experienced at least one grade 3-5 toxicity, most commonly diarrhoea (14 patients), dehydration (7 patients) and lethargy (6 patients). The 12 week progression-free survival rate was 16.7 % (95 % CI 6.1 %-36.5 %) in the 24 patients with a 12 week scan available or who had died prior to the 12 week scan. No complete or partial responses were seen by 12 weeks. The median progression-free survival was 2.6 months (95 % CI 2.3-2.9) and median overall survival was 6.1 months (95 % CI 3.7-8.4). Conclusion Patupilone given at a dose of 8 mg/m IV over 20 min every 3 weeks was associated with high levels of toxicity and no significant evidence of efficacy in patients with pre-treated colorectal cancer. [ABSTRACT FROM AUTHOR]

Background:Bisphosphonates are the most commonly prescribed osteoporosis drugs but long-term effects are unclear, although antitumour properties are known from preclinical studies.Methods:Nested case-control studies were conducted to investigate bisphosphonate use and risks of common non-gastrointestinal cancers (breast, prostate, lung, bladder, melanoma, ovarian, pancreas, uterus and cervical). Patients 50 years and older, diagnosed with primary cancers between 1997 and 2011, were matched to five controls using the UK practice-based QResearch and Clinical Practice Research Datalink (CPRD) databases. The databases were analysed separately and the results combined.Results:A total of 91 556 and 88 845 cases were identified from QResearch and CPRD, respectively. Bisphosphonate use was associated with reduced risks of breast (odds ratio (OR): 0.92, 95% confidence interval (CI): 0.87-0.97), prostate (OR: 0.87, 95% CI: 0.79-0.96) and pancreatic (OR: 0.79, 95% CI: 0.68-0.93) cancers in the combined analyses, but no significant trends with duration. For alendronate, reduced risk associations were found for prostate cancer in the QResearch (OR: 0.81, 95% CI: 0.70-0.93) and combined (OR: 0.84, 95% CI: 0.75-0.93) analyses (trend with duration P-values 0.009 and 0.001). There were no significant associations from any of the other analyses.Conclusion:In this series of large population-based case-control studies, bisphosphonate use was not associated with increased risks for any common non-gastrointestinal cancers. [ABSTRACT FROM AUTHOR]

There is a drive in the UK to revise chemotherapy provision for people living in rural communities. Using a different model of treatment delivery might impact positively upon the experience of receiving chemotherapy. In 2007 the first nurse-led mobile chemotherapy unit ( MCU) in the UK was launched in the South West of England with the intention of providing treatment closer to home. The aim of the research was to explore experiences of people with cancer who received chemotherapy treatment in outpatient clinic and/or onboard the MCU using an interpretive phenomenological approach. Interviews were conducted with 20 people and data were interpreted using thematic analysis. The cancer and chemotherapy journey was described as being undertaken by the participant and their significant other. Available car parking and travelling impacted upon quality of life, as did the environment and accessibility of nurses to discuss issues with participants. The most important, distinguishing feature between receiving chemotherapy in outpatient clinic and the MCU was the amount of time spent waiting. Having treatment on the MCU was perceived to be less formal and therefore less stressful. Participants reported significant savings in time spent travelling, waiting and having treatment, expenditure on fuel and companion costs. [ABSTRACT FROM AUTHOR]

The efficacy of saline washout technique in the management of exfoliant and vesicant chemotherapy extravasationa historical case series report This report presents the results from a historical case series of cytotoxic drug extravasations managed by saline washout; its purpose is to assess the efficacy of the procedure based on patient outcome. Eighty-nine patients were identified as having experienced a vesicant or exfoliant extravasation from incident reports filed over a 10-year period, from 1 April 2001 to 31 March 2011. Outcome was measured against the need for further surgical treatment being required. Of the 89 cases assessed for efficacy of saline washout one patient experienced a wound infection, which was treated effectively with oral antibiotics. There were no other complications reported and no patients required further treatment with surgical debridement. The majority of patients had no deferral of treatment as chemotherapy could be continued in their unaffected arm immediately following saline washout procedure. For patients where cannulation in their opposite arm for continuation of treatment was not advisable chemotherapy was delayed between 3 and 7 days. Hospitalisation as a result of the extravasation or subsequent treatment was not required in any of the 89 cases. Results indicate that saline washout technique is a safe and effective management strategy for the treatment of both vesicant and exfoliant chemotherapy extravasation. [ABSTRACT FROM AUTHOR]

In this article, the author reflects on the implications of the plans of health secretary Andrew Lansley to introduce 50 million British pounds into cancer drugs fund for cancer research in Great Britain.

Background: Thymoma and thymic carcinoma are relatively rare tumours of the anterior mediastinum. Optimum treatment options for these tumours remain unresolved, although at present, a multimodality approach involving aggressive surgical resection, platinum-based combination chemotherapeutic interventions and radiotherapy represents the preferred therapeutic approach.1-3 This study evaluates the treatment outcome of patients with thymic tumours at our centre. Methods: We retrospectively reviewed clinical case notes, electronic patient records, imaging and radiation treatment records of patients treated at Clatterbridge Cancer Centre. Results: A total of 21 patients diagnosed with thymic tumours were treated at Clatterbridge Cancer Centre between June 1990 until June 2011. There were 12 (57%) out of 21 patients who received multimodality therapy (chemotherapy and/or radiation therapy and/or surgery), 7 (34%) received single modality treatment and 2 (9%) did not receive any treatment. Relapse occurred in 10 (47%) patients with a median time from primary diagnosis to relapse of 28 months (10 to 104 months). Among those who relapsed, 6 died with a median survival of 58 months (53 to 64 months). Out of 12 patients in the multimodality treatment group, 9 (75%) remain alive with a median follow up of 45 months. In 7 patients who received single mode therapy, 5 (71%) died with a median survival of 45 months. 2 patients who did not receive any treatment died. Overall median survival in 10 of 21 patients who died was 42 months (2 to 192 months). Conclusion: Multimodality treatment for thymic tumours represents the preferred therapeutic approach and should be considered in suitable patients. Further randomized trials are necessary to define the optimum treatment options. [ABSTRACT FROM AUTHOR]

Data for 25261 patients with non-small cell lung cancer whose details were submitted to the National Lung Cancer Audit in England were analysed to assess the effect of age at diagnosis on their clinical management, after accounting for sex, stage, performance status and comorbidity. Multivariate logistic regression showed the odds of having histocytological confirmation and anticancer treatment decreased progressively with age, and was also lower in women. It is likely that these results have a multifactorial explanation, and further research into the attitudes of patients, carers and healthcare professionals, and clinical trials of treatment in older populations, are necessary. [ABSTRACT FROM AUTHOR]

The prevalence of breast cancer is increasing as more women are living with the disease. Outcomes have improved as a result of progress in all major aspects of multidisciplinary care. These include surgery, radiotherapy, hormonal therapy, chemotherapy and newer targeted drugs. Two aspects merit particular attention here. First, there is an understanding now that cancer is a heterogenous disease and a 'one-size-fits-all' approach is becoming redundant, albeit slowly. Second, basic science and an appreciation of cellular molecular targets in those different types of breast cancer is being translated into the clinic and has led to the development of exciting new drugs for both triple negative and HER2-positive relapsed disease. An improved understanding of endocrine resistance remains an unmet need in drug development and here, it appears worthwhile to adopt less conventional approaches. Better trial design with a focus on biomarkers should lower barriers to regulatory approval as well as increase cost effectiveness. [ABSTRACT FROM AUTHOR]

Ovarian cancer is the fourth most common cause of cancer death among women. It has a poor prognosis, withfive-year survival rates of 40 per cent. This article discusses early symptoms and treatments. It explores themanagement of disease, treatment-related symptoms and end of life care and provides practical guidance on ways in which cancer nurses can work in partnership with women to support and educate them to self-manage their symptoms where possible and deal with the challenges posed by their illness. [ABSTRACT FROM AUTHOR]

It is known that adverse drug reactions (ADRs) cause admission to hospital in adults and children. A recent adult study showed that ADRs are an important and frequent cause of hospital admission. The objective of this study is to develop methodology to ascertain the current burden of ADRs through a prospective analysis of all unplanned admissions to a paediatric hospital. Prospective observational study over a 2-week period. There were 19 admissions to the main hospital wards related to an ADR, giving an estimated incidence of 4%, with the ADR directly leading to the admission in 71% of cases. There were no deaths attributable to ADR. 33% of the reactions were possibly avoidable. The drugs most commonly implicated in causing admissions were anti-neoplastic agents. The most common reactions were neutropenia, vomiting and diarrhoea. The health burden of ADRs in the paediatric population is likely to be significant. This pilot study will be used to inform a much larger prospective study providing more detailed evidence of the burden of ill-health from ADRs in children. This larger study will add to a body of research aiming to identify drug-related problems within children to aid paediatric pharmacovigilance. This study provides knowledge regarding the methodology to be used for a larger study investigating ADRs in children. The study will allow authors who wish to replicate the study in their own populations (internationally) to avoid some of the pitfalls in planning a large epidemiological study of paediatric ADRs. The study also provides an estimate of the incidence and problem of admissions caused by ADRs in a UK paediatric population. [ABSTRACT FROM AUTHOR]

The article discusses the Hazardous Waste Regulations 2005, regulations related to the disposal of veterinary wastes. The regulations make it mandatory for all veterinary practices producing more than 200 kg of waste a year to register with the Environment Agency of Great Britain. The segregation and disposal of waste has strict rules to follow. Special rules related to the disposal of cytotoxic drugs and animal carcases are also included in the regulations.

The author argues against the inequalities in Great Britain's healthcare system as represented in the Cancer Drugs Fund (CDF), which is solely dedicated to extending the use of cancer drugs regardless of their clinical and cost effectiveness. He says the CDF's existence is contrary to the healthcare system's founding principle of providing equal medical access. He also says that such realignment imposes ethical, health and economic implications as a direct consequence of such inequity.

Background: Epigenetic silencing of O(6)-methylguanine-DNA-methyltransferase (MGMT) by promoter methylation is associated with improved survival in glioblastomas treated with alkylating agents. In this study, we investigated MGMT promoter methylation in glioblastomas treated with temozolomide and radiotherapy in a single UK treatment centre.Methods: Quantitative methylation data at individual CpG sites were obtained by pyrosequencing for 109 glioblastomas.Results: Median overall survival (OS) was 12.4 months with 2-year survival of 17.9%. Pyrosequencing data were reproducible with archival samples yielding data for all glioblastomas. Variation in methylation patterns of discrete CpG sites and intratumoral methylation heterogeneity were observed. A total of 58 out of 109 glioblastomas showed average methylation >non-neoplastic brain in at least one clinical sample; 86% had homogeneous methylation status in multiple samples. Methylation was an independent prognostic factor associated with prolonged progression-free survival (PFS) and OS. Cases with methylation more than 35% had the longest survival (median PFS 19.2; OS 26.2 months, 2-year survival of 59.7%). Significant differences in PFS were seen between those with intermediate or high methylation and unmethylated cases, whereas cases with low, intermediate or high methylation all showed significantly different OS.Conclusions: These data indicate that MGMT methylation is prognostically significant in glioblastomas given chemoradiotherapy in the routine clinic; furthermore, the extent of methylation may be used to provide additional prognostic stratification. [ABSTRACT FROM AUTHOR]

We present the preliminary toxicity data from the MRC COIN trial, a phase III randomised controlled trial of first-line therapy in advanced colorectal cancer, with particular reference to the addition of cetuximab to an oxaliplatin-fluoropyrimidine combination. A total of 804 patients were randomised between March 2005 and July 2006 from 78 centres throughout the United Kingdom. Patients were allocated to oxaliplatin plus fluoropyrimidine chemotherapy with or without the addition of weekly cetuximab. The choice of fluoropyrimidine (either 5-fluorouracil (5FU) or capecitabine) was decided by the treating physician and patient before randomisation. Toxicity data were collected from all patients. Two hundred and three patients received 5FU plus oxaliplatin (OxMdG, 25%), 333 oxaliplatin+capecitabine (Xelox, 41%), 102 received OxMdG+cetuximab (OxMdG+C, 13%) and 166 Xelox+cetuximab (21%). Percent grade 3/4 toxicities included diarrhoea 6, 15, 13 and 25%, nausea/vomiting 3, 7, 7 and 14% for OxMdG, Xelox, OxMdG+C and Xelox+C, respectively. Sixty-day all-cause mortality was 6, 5, 5 and 7%. Statistically significant differences were evident for patients receiving Xelox+cetuximab vs Xelox alone: diarrhoea relative risk (RR) 1.69 (1.17, 2.43, P=0.005) and nausea/vomiting RR 2.01 (1.16, 3.47, P=0.012). The excess toxicity observed in the oxaliplatin-, capecitabine-, cetuximab-treated patients led the trial management group to conclude that a capecitabine dose adjustment was required to maintain safety levels when using this regimen. [ABSTRACT FROM AUTHOR]

In the UK, 10% of patients diagnosed with rectal cancer have inoperable disease at presentation. This study ascertained whether the resectability rate of inoperable locally advanced rectal cancer was improved by administration of intravenous irinotecan, 5-fluorouracil (5-FU) and pelvic radiotherapy. During phase I of the trial (n=12), the dose of irinotecan was escalated in three-patient cohorts from 50 mg m(-2) to 60 mg m(-2) to 70 mg m(-2) to identify the maximum tolerated dose (60 mg m(-2)). In phase II, 31 patients with non-resectable disease received 45 Gy radiotherapy and 5-FU infusions (200 mg m(-2) per day) for 5 weeks. Irinotecan (60 mg m(-2)) was given on days 1, 8, 15 and 22. After treatment, patients were operated on if possible. Thirty patients completed the protocol, 28 underwent surgery. Before surgery, MRI restaging of 24 patients showed that 19 (79%) had a reduction in tumour stage after treatment (seven complete clinical response and 12 partial). Of 27 patients followed up after surgery, 22 (81%) had clear circumferential resection margins. Disease-free and overall survival estimates at 3 years were 65 and 90%, respectively. The regimen was well tolerated. Irinotecan, 5-FU and radiotherapy results in tumour downgrading, allowing resection of previously inoperable tumour with acceptable toxicity. [ABSTRACT FROM AUTHOR]

Promiscuous expression of tissue-restricted auto-antigens in the thymus imposes T-cell tolerance and provides protection from autoimmune diseases. Promiscuous expression of a set of self-antigens occurs in medullary thymic epithelial cells and is partly controlled by the autoimmune regulator (AIRE), a nuclear protein for which loss-of-function mutations cause the type 1 autoimmune polyendocrine syndrome. However, additional factors must be involved in the regulation of this promiscuous expression. Here we describe a mechanism controlling thymic transcription of a prototypic tissue-restricted human auto-antigen gene, CHRNA1. This gene encodes the α-subunit of the muscle acetylcholine receptor, which is the main target of pathogenic auto-antibodies in autoimmune myasthenia gravis. On re-sequencing the CHRNA1 gene, we identified a functional bi-allelic variant in the promoter that is associated with early onset of disease in two independent human populations (France and United Kingdom). We show that this variant prevents binding of interferon regulatory factor 8 (IRF8) and abrogates CHRNA1 promoter activity in thymic epithelial cells in vitro. Notably, both the CHRNA1 promoter variant and AIRE modulate CHRNA1 messenger RNA levels in human medullary thymic epithelial cells ex vivo and also in a transactivation assay. These findings reveal a critical function of AIRE and the interferon signalling pathway in regulating quantitative expression of this auto-antigen in the thymus, suggesting that together they set the threshold for self-tolerance versus autoimmunity. [ABSTRACT FROM AUTHOR]

The National Institute for Health and Clinical Excellence recommends vinorelbine (VNB), paclitaxel, docetaxel, and gemcitabine in the treatment of non-small cell lung cancer. An economic model was prepared to determine the comparative cost of these agents, including the new oral formulation of VNB from a United Kingdom National Health System perspective. Clinical effectiveness was determined from published trials. Costs of drug acquisition, administration, toxicity management, and patient transportation costs were calculated from reference publications. A Markov model was used to estimate the cost per patient over 52 weeks. Intravenous VNB, gemcitabine, paclitaxel, and docetaxel incur annual follow-up costs of 3,746 pounds, 5,332 pounds, 5,977 pounds, and 6,766 pounds, respectively, while oral VNB with outpatient administration on d1, and self-administration at home on d8 every 21 days has a cost per patient per year of 2,888 pounds. Oral VNB allows further hospital resources savings. [ABSTRACT FROM AUTHOR]

Background: MA17 was a randomised placebo-controlled trial of letrozole 2.5 mg/day in 5187 estrogen receptor-positive, 50% node-negative, postmenopausal women (median age 62 years at enrollment) with early breast cancer, post-5 years' adjuvant tamoxifen therapy. The objective of this evaluation was to extrapolate the findings from the MA17 trial to estimate the lifetime cost effectiveness of letrozole in this setting.Methods: A Markov model was used to estimate the incremental cost per QALY gained with extended adjuvant letrozole versus no therapy. Probabilities of disease progression and death were estimated using data from the MA17 study and other secondary sources. Costs of breast cancer care (letrozole therapy, surveillance, recurrences, terminal care) and treatment of osteoporosis and utilities were derived from literature. A full probabilistic sensitivity analysis was undertaken. The analysis was conducted from the perspective of the UK National Health Service (NHS) and cost estimates reflect 2004 values. All costs and outcomes were discounted at 3.5%.Results: Extended adjuvant letrozole resulted in a gain of 0.36 QALYs per patient (13.66 vs 13.30 with no therapy). These benefits were obtained at an additional expected lifetime cost of 3732 pounds per patient (10,833 pounds letrozole vs 7101 pounds with no therapy). Cost effectiveness was estimated at 10,338 pounds per QALY gained (95% CI 5276, 43,828). The results were robust to sensitivity analyses.Conclusion: Five years of letrozole therapy appears to be cost effective from the NHS perspective and should be considered in women with early breast cancer, following tamoxifen adjuvant therapy. [ABSTRACT FROM AUTHOR]

Many cancer patients use complementary alternative medicines (CAMs) but may not be aware of the potential risks. There are no studies quantifying such risks, but there is some evidence of patient risk from case reports in the literature. A cross-sectional survey of patients attending the outpatient department at a specialist cancer centre was carried out to establish a pattern of herbal remedy or supplement use and to identify potential adverse side effects or drug interactions with conventional medicines. If potential risks were identified, a health warning was issued by a pharmacist. A total of 318 patients participated in the study. Of these, 164 (51.6%) took CAMs, and 133 different combinations were recorded. Of these, 10.4% only took herbal remedies, 42.1% only supplements and 47.6% a combination of both. In all, 18 (11.0%) reported supplements in higher than recommended doses. Health warnings were issued to 20 (12.2%) patients. Most warnings concerned echinacea in patients with lymphoma. Further warnings were issued for cod liver/fish oil, evening primrose oil, gingko, garlic, ginseng, kava kava and beta-carotene. In conclusion, medical practitioners need to be able to identify the potential risks of CAMs. Equally, patients should be encouraged to disclose their use. Also, more research is needed to quantify the actual health risks.British Journal of Cancer (2004) 90, 408-413. doi:10.1038/sj.bjc.6601560 www.bjcancer.com [ABSTRACT FROM AUTHOR]

This study evaluated the cost-effectiveness of gemcitabine as first-line treatment for pancreatic cancer in the UK. Outcomes data and costs based on utilisation data were analysed from a previously reported clinical trial. Outcome measures were average and incremental costs of survival gain, progression-free survival gain and clinical benefit response (a symptom-based measure) for gemcitabine compared with 5-fluorouracil (5-FU) via intravenous injection in the first-line setting. The incremental costs per life-year and per progression-free life-year were £12,206 and £19,888, respectively, for gemcitabine over 5-FU therapy. The incremental cost per clinical benefit responder for gemcitabine over 5-FU was £12,142. If 5-FU was administered by 24-h continuous infusion rather than being given once a week, treatment costs were estimated to be more expensive. The resulting incremental cost per life-year gained with gemcitabine falls to £8,831. Sensitivity analyses (including alterations based on statistical variance) demonstrated that the results were robust and relatively insensitive to variations in key parameters. Gemcitabine is thus a cost-effective therapy for patients with pancreatic cancer and cost per life-year compares favourably with other technologies funded by the National Health Service in the UK. [ABSTRACT FROM AUTHOR]

Background: The prognosis of non-Hodgkin lymphoma and Hodgkin lymphoma is not affected by HIV serostatus, yet people living with HIV (PLWH) are frequently excluded from clinical trials in lymphoma.Methods: The UK NIHR Clinical Research Network Study Portfolio website was used to identify all the open clinical trials in lymphoma in the United Kingdom in January 2015. Trials that excluded PLWH were further investigated to evaluate if the exclusion was justified by scientific evidence.Results: We identified 56 multicentre open clinical trials in lymphoma including 46 interventional trials. People living with HIV were excluded from 32 interventional trials (70%). We identified a biologically valid reason (a potential increased risk of greater immunosuppression) for excluding PLWH from one trial and possibly for one optional arm in another study.Conclusions: There was no scientific or safety justification for excluding PLWH from most lymphoma clinical trials included on the NIHR portfolio. A clear justification for excluding PLWH was not offered in the available protocols. The exclusion of PLWH should be explicitly justified on scientific grounds in protocols to minimise stigmatisation. [ABSTRACT FROM AUTHOR]

Aim HER2 status is vital for selecting breast cancer patients for trastuzumab treatment. One recommended approach is to assess immunohistochemical staining and then perform in situ hybridisation on those tumours with a borderline (2+) immunohistochemical result. This audit aimed to assess the value of the percentage of immunohistochemical staining in 2+ tumours in selecting tumours for in-situ hybridisation. Methods HER2 immunohistochemistry and in situ hybridisation was performed according to UK guidelines. The percentage of complete membrane staining of invasive carcinoma cells for HER2 was recorded as part of routine reporting. Results 191 (11%) of 1735 invasive carcinomas were scored as 3+. 419 (24%) were scored as 2+. 57 of 413 2+ carcinomas (14%) were amplified (ratio of HER2 to chromosome 17≥2.0). The frequency of amplification was related to the percentage of complete membrane staining: eight of 149 (5%) with 10-19% membrane staining, 11 of 93 (12%) with 20-29% staining, 26 of 150 (17%) with 30-79% staining and 12 of 21 (57%) with 80-100% staining. Conclusions This audit suggests that increasing the threshold for 2+ from 10% to 20% complete membrane staining would reduce the number of in-situ hybridisation tests by 36%, but reduce the detection of amplified tumours by 14%. [ABSTRACT FROM AUTHOR]

The article discusses the potential use of closed-system transfer devices (CSTDs) for the safe handling of drugs in Great Britain as a means of preventing the transmission of environmental contaminants into patients and the release of hazardous concentrations of drugs or vapour. Best-practice guidelines for nurses and pharmacy staff members are examined, along with the United Kingdom Oncology Society (UKONS) and workplace safety concerns and systemic anti-cancer therapy (SACT).