Ablative therapy for people with localised prostate cancer: a systematic review and economic evaluation

© Queen’s Printer and Controller of HMSO 2015.Background People diagnosed with cancer of the prostate, a sex gland in the pelvis, have a choice of treatment options depending on the severity of disease. For people whose cancer is at medium and low risk of spread, the main options are surgical removal of the prostate, radical prostatectomy (RP), use of external beam radiotherapy (EBRT) to destroy the cancer or delaying treatment until there are signs that the cancer is getting worse [active surveillance (AS)]. RP and radiotherapy are effective at curing the cancer but may also cause long-term urinary incontinence and sexual problems. AS, on the other hand, may be quite difficult for people to cope with as they know that the cancer is still present. Newer treatments aim to target the disease more precisely so that surrounding normal tissues can be preserved, reducing the risk of side effects but still effectively destroying the cancer. These more targeted ablative therapies include cryotherapy, high-intensity focused ultrasound (HIFU), brachytherapy, photodynamic therapy (PDT), radiofrequency interstitial tumour ablation (RITA) and laser therapy, among others. Aims This study aimed to develop clinical care pathways relevant to a UK NHS context review systematically the evidence of the clinical effectiveness and safety of each newer ablative therapy concerning primary and salvage treatment of localised prostate cancer• determine which therapies are most likely to be cost-effective for implementation in the UK NHS identify and prioritise future research needs. Methods Clinical effectiveness review We conducted two discrete systematic reviews: (a) primary ablative treatment of localised prostate cancer compared with AS, RP or EBRT (b) salvage ablative treatment for local prostate cancer relapse after primary EBRT compared with salvage RP. MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, Bioscience Information Service (BIOSIS), Science Citation Index, Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database of Systematic Reviews (CDSR), Database of Abstracts of Reviews of Effects (DARE) and the Health Technology Assessment (HTA) databases were searched to the end of March 2013. Reference lists of all included studies were scanned and experts on our advisory panel were contacted for details of additional reports. Evidence came from randomised controlled trials (RCTs), non-randomised comparative studies (NRCSs) (if no RCT evidence was identified) and single-arm cohort studies (case series) with greater than 10 participants for the ablative procedures only. Conference abstracts or non-English-language reports were excluded. For the primary therapy systematic review, the ablative therapies considered were cryotherapy, HIFU, PDT, RITA, laser ablation and brachytherapy. The comparators were AS, RP and EBRT. For the salvage therapy systematic review, the ablative therapies considered were cryotherapy and HIFU. The comparator was RP. Outcomes were cancer related, adverse effects (functional and procedural) and quality of life. Two reviewers extracted data and carried out quality assessment. For meta-analysis, a Bayesian indirect mixed-treatment comparison was used. Cost-effectiveness The cost-effectiveness of the different treatments and their subsequent care pathways was assessed using a modified Markov individual simulation model, applied to a UK NHS setting. The perspective for the model was a health services perspective. Parameter estimates were derived from the systematic review of clinical effectiveness, a micro-costing exercise, other literature, the expert advisory group and other UK sources. The outputs of the model were costs and quality-adjusted life-years (QALYs) for each procedure, incremental costs and QALYs and incremental cost per QALY over the remaining lifetime. Both costs and QALYs were discounted at 3.5%. An elasticity analysis, together with probabilistic and deterministic sensitivity analyses, were performed to explore the uncertainty surrounding parameter estimates. Results Clinical effectiveness Cryotherapy Data from 3995 patients who received cryotherapy across 19 studies (1 RCT, 4 NRCSs and 14 case series) were included, with most studies considered to be at high risk of bias. In the short term, there was conflicting evidence relating to cancer-specific outcomes when cryotherapy was compared with either EBRT or surgery. The only finding that reached statistical significance was 1-year disease-free survival, which was worse for cryotherapy than for either EBRT or RP. However, none of the other cancer-specific outcomes, such as biochemical failure or overall survival, showed any significant differences between them. The findings in relation to cancer-specific outcomes are best regarded as inconclusive. There was evidence that the rate of urinary incontinence at 1 year was lower for people undergoing cryotherapy than for those undergoing RP [3% vs. 66%; odds ratio (OR) 0.02, 95% credible interval (CrI) < 0.01 to 0.34], but the size of the difference decreased with longer follow-up. There was a general trend for cryotherapy to have fewer procedural complications, apart from urinary retention. The only difference that reached statistical significance was for urethral stricture, which was less frequent after cryotherapy than after RP (1% vs. 8%; OR 0.24, 95% CrI 0.09 to 0.54). High-intensity focused ultrasound Data from 4000 patients who received HIFU across 21 studies (1 NRCS and 20 case series) were included, with all studies considered to be at high risk of bias. There was some evidence that biochemical failure rates were higher at 1 year when using HIFU than when using EBRT, and this was statistically significant. However, the difference was no longer statistically significant at 5 years. Similar findings were observed with regard to disease-free survival at 1 year, with worse outcomes for HIFU than for EBRT, which were statistically significant. The differences were no longer significant at 3 years. The biochemical result was in contrast to overall survival at 4 years, which was higher when using HIFU. There were insufficient data on any urinary incontinence, erectile dysfunction or bowel problems to draw any robust conclusions, although at 1 year HIFU had lower incontinence rates than RP (10% vs. 66%; OR 0.06, 95% CrI 0.01 to 0.48). The safety profile for HIFU was generally good, apart from a potential numerical increase in rates of urinary retention and dysuria. However, HIFU appeared to have a slightly higher incidence of urethral stricture than EBRT, and the difference was statistically significant (8% vs. 1%; OR 5.8, 95% CrI 1.2 to 24.5). Brachytherapy This review considered data from 26,129 patients who received brachytherapy across 40 studies (2 RCTs and 38 NRCSs), with most studies considered to be at high risk of bias. The data for brachytherapy were generally more robust than for other ablative therapies. In the short term, there was some evidence at 5-year follow-up that the rate of biochemical failure was lower for brachytherapy (7%) than for EBRT (13%; OR 0.46, 95% CrI 0.32 to 0.67) or RP (11%; OR 0.35, 95% CrI 0.21 to 0.56). There was also some evidence that disease-free survival was better for brachytherapy at 3-year follow-up. There was evidence that the rate of urinary incontinence up to 5 years after treatment was lower for people undergoing brachytherapy than for RP, but the size of the difference decreased with longer follow-up. There was also a trend towards lower erectile dysfunction rates for brachytherapy than for EBRT or RP and this reached statistical significance at 3 years after treatment (60% vs. 81% for EBRT and 88% for RP). There were insufficient data to draw any conclusions on bowel problems. The findings regarding procedural complications were mixed. Dysuria rates were higher for brachytherapy and this reached statistical significance when compared with RP. Urinary retention was also statistically significantly higher for brachytherapy than for EBRT. Stricture rates for brachytherapy were higher than those for EBRT, but lower than those for RP. The differences for stricture reached statistical significance when compared with RP. For rectal pain, there was evidence that rates were significantly lower for brachytherapy than for EBRT. Acute genitourinary toxicity, though rare, had statistically higher rates for brachytherapy than for EBRT, but acute gastrointestinal toxicity was lower for brachytherapy. Other ablative therapies Only two other ablative therapies were identified in the review: focal laser ablative therapy and PDT. Data were too scarce (a total of 35 participants for these two procedures) for any conclusions. Salvage therapy Data from 400 participants who were treated with salvage therapy following primary EBRT across nine case series were included. Six studies involved salvage RP, two involved salvage cryotherapy and one involved salvage HIFU. In six studies, data were not collected prospectively, and only short-term outcomes were reported. As such, all of the studies were considered as having a high risk of bias. There was no robust evidence that mortality or other cancer-specific outcomes differed between salvage cryotherapy and salvage RP in the short term. There were no data on cancer-specific outcomes for salvage HIFU. In regard to functional and quality of life outcomes, lack of data prevented any conclusions. In terms of adverse event outcomes, salvage cryotherapy had numerically fewer periprocedural complications (especially for bladder neck stenosis) than salvage HIFU or salvage RP, but there was a high level of uncertainty with this observation. Focal ablation Descriptive subgroup assessment within studies reporting the use of focal ablation was limited, but suggested that cancer-specific outcomes were at least comparable with those seen in full-gland therapy studies. Urinary incontinence rates may be lower following focal ablation, but the evidence is weak in light of the poor quality and quantity of the data. Active surveillance Lack of outcome data prevented comparison of the efficacy of ablative therapies with a programme of AS, apart from the rate of erectile dysfunction at 12 months, where there was no statistically significant difference. Cost-effectiveness Assuming equal recurrence in line with the lack of statistical differences from the effectiveness review, EBRT was the least costly (£19,363 per patient) and least effective (3.63 QALYs), whereas HIFU was more costly (£19,860 per patient) and more effective (3.86 QALYs). HIFU was more effective and less costly than the other newer ablative interventions. The lifetime incremental cost per QALY for HIFU compared with EBRT was £2915. There was a 75% chance that HIFU would be considered cost-effective at a £30,000-per-QALY threshold. In a plausible best-and-worst-case analysis, the probability that HIFU would be considered cost-effective varied between 60% and 70%. Strengths and limitations The main strength of the study was the systematic approach taken to review the literature and the inclusion of a relatively large quantity of studies, giving a high total number of participants. The main limitations were the low quantity and poor quality of the data available on cancer-related outcomes and long-term adverse events of urinary incontinence, sexual and bowel dysfunction, and the changing technology over the review period. Many published studies were poorly reported or lacked sufficient detail. Inconsistency in outcome definition, measurement and reporting was also a significant problem, and much of the information available was unsuitable for meta-analysis. Another major limitation resulted from the majority of comparisons being made using case series, with few head-to-head comparisons of ablative therapies against current practice. The estimates were therefore generated using indirect comparisons. Like all analyses, they require assumptions to be made that may or may not be reasonable. Accordingly, the results should be interpreted with a large degree of caution. Despite the considerable efforts to construct a model and seek the best data available, the lack of effectiveness data had implications for the economic evaluation. The limited data meant that there was insufficient evidence to assume that there was any difference between interventions for a number of parameters, a particular issue for biochemical recurrence, which was a key parameter in the evaluation. The impact of these assumptions was explored in sensitivity analyses. Conclusions Implications for health care For primary ablative therapy, neither cryotherapy nor HIFU had sufficiently robust data to enable any definitive conclusions to be made. The effectiveness data on brachytherapy were more robust and there was some evidence that cancer-specific outcomes in the short term were either better or equivalent to either EBRT or RP, with comparable adverse effect profiles apart from a possible increased risk of dysuria and urinary retention. The findings on focal ablative therapy were mostly derived from data on focal cryotherapy, which suggested that cancer-specific outcomes were at least comparable with those of full-gland cryotherapy, and there was a suggestion that the urinary incontinence outcome may be better following focal cryotherapy than whole-gland cryotherapy. The cost-effectiveness analysis confirmed the uncertainty from the clinical review and that there is no technology which appears superior, on the basis of current evidence, in terms of average cost-effectiveness. The probabilistic sensitivity analyses suggest that a number of ablative techniques are worthy of further research. For salvage ablative therapy following primary EBRT, a lack of reliable and robust data prevented any meaningful conclusions from being made, in comparison with salvage RP. The findings from the review indicate that there is insufficient evidence to help inform recommendations on the use of ablative therapies in the UK NHS. Need for further research The main gaps in the evidence base are the lack of direct comparative studies of ablative therapies; the consequent lack of robust data to inform calculations of cost-effectiveness and the role of focal ablative therapies; and the lack of longer-term data on cancer control, such as overall and cancer-specific mortality. The key research recommendations, in order of importance, are as follows: 1. HIFU and brachytherapy seem the most promising newer interventions but they lack high-quality evaluation. Such evaluation should ideally be by multicentre RCT with long-term follow-up, and would include predefined assessment of cancer-specific, dysfunction and health-related quality-of-life measures. Such studies should incorporate economic evaluations and also inform economic modelling

Implementation of the 2017 Berlin Concussion in Sport Group Consensus Statement in contact and collision sports: a joint position statement from 11 national and international sports organisations.

The 2017 Berlin Concussion in Sport Group Consensus Statement provides a global summary of best practice in concussion prevention, diagnosis and management, underpinned by systematic reviews and expert consensus. Due to their different settings and rules, individual sports need to adapt concussion guidelines according to their specific regulatory environment. At the same time, consistent application of the Berlin Consensus Statement's themes across sporting codes is likely to facilitate superior and uniform diagnosis and management, improve concussion education and highlight collaborative research opportunities. This document summarises the approaches discussed by medical representatives from the governing bodies of 10 different contact and collision sports in Dublin, Ireland in July 2017. Those sports are: American football, Australian football, basketball, cricket, equestrian sports, football/soccer, ice hockey, rugby league, rugby union and skiing. This document had been endorsed by 11 sport governing bodies/national federations at the time of being published

Dysbindin Promotes the Post-Endocytic Sorting of G Protein-Coupled Receptors to Lysosomes

BackgroundDysbindin, a cytoplasmic protein long known to function in the biogenesis of specialized lysosome-related organelles (LROs), has been reported to reduce surface expression of D2 dopamine receptors in neurons. Dysbindin is broadly expressed, and dopamine receptors are members of the large family of G protein-coupled receptors (GPCRs) that function in diverse cell types. Thus we asked if dysbindin regulates receptor number in non-neural cells, and further investigated the cellular basis of this regulation.Methodology/principal findingsWe used RNA interference to deplete endogenous dysbindin in HEK293 and HeLa cells, then used immunochemical and biochemical methods to assess expression and endocytic trafficking of epitope-tagged GPCRs. Dysbindin knockdown up-regulated surface expression of D2 receptors compared to D1 receptors, as reported previously in neurons. This regulation was not mediated by a change in D2 receptor endocytosis. Instead, dysbindin knockdown specifically reduced the subsequent trafficking of internalized D2 receptors to lysosomes. This distinct post-endocytic sorting function explained the minimal effect of dysbindin depletion on D1 receptors, which recycle efficiently and traverse the lysosomal pathway to only a small degree. Moreover, dysbindin regulated the delta opioid receptor, a more distantly related GPCR that is also sorted to lysosomes after endocytosis. Dysbindin was not required for lysosomal trafficking of all signaling receptors, however, as its depletion did not detectably affect down-regulation of the EGF receptor tyrosine kinase. Dysbindin co-immunoprecipitated with GASP-1 (or GPRASP-1), a cytoplasmic protein shown previously to modulate lysosomal trafficking of D2 dopamine and delta opioid receptors by direct interaction, and with HRS that is a core component of the conserved ESCRT machinery mediating lysosome biogenesis and sorting.Conclusions/significanceThese results identify a distinct, and potentially widespread function of dysbindin in promoting the sorting of specific GPCRs to lysosomes after endocytosis

Defining the expression hierarchy of latent T-cell epitopes in Epstein-Barr virus infection with TCR-like antibodies

Epstein-Barr virus (EBV) is a gamma herpesvirus that causes a life-long latent infection in human hosts. The latent gene products LMP1, LMP2A and EBNA1 are expressed by EBV-associated tumors and peptide epitopes derived from these can be targeted by CD8 Cytotoxic T-Lymphocyte (CTL) lines. Whilst CTL-based methodologies can be utilized to infer the presence of specific latent epitopes, they do not allow a direct visualization or quantitation of these epitopes. Here, we describe the characterization of three TCR-like monoclonal antibodies (mAbs) targeting the latent epitopes LMP1[subscript 125–133], LMP2A[subscript 426–434] or EBNA1[subscript 562–570] in association with HLA-A0201. These are employed to map the expression hierarchy of endogenously generated EBV epitopes. The dominance of EBNA1[subscript 562–570] in association with HLA-A0201 was consistently observed in cell lines and EBV-associated tumor biopsies. These data highlight the discordance between MHC-epitope density and frequencies of associated CTL with implications for cell-based immunotherapies and/or vaccines for EBV-associated disease

Risk of breast cancer in young women in relation to body size and weight gain in adolescence and early adulthood

Findings have been inconsistent on effects of adolescent body size and adult weight gain on risk of breast cancer in young women. These relations were examined in a population-based case control study of 1590 women less than 45 years of age newly diagnosed with breast cancer during 1990–1992 in three areas of the US and an age-matched control group of 1390 women. Height and weight were measured at interview and participants asked to recall information about earlier body size. Logistic regression was used to estimate the relative risk of breast cancer adjusted for other risk factors. Women who were either much heavier or lighter than average in adolescence or at age 20 were at reduced risk. Weight gain after age 20 resulted in reduced risk, but the effect was confined to early-stage and, more specifically, lower grade breast cancer. Neither the risk reduction nor the variation by breast cancer stage or grade was explained by the method of cancer detection or by prior mammography history. These findings suggest that relations between breast cancer risk in young women and body weight at different ages is complex and that the risk reduction with adult weight gain is confined to less aggressive cancers. © 1999 Cancer Research Campaig

Clonal Structure of Rapid-Onset MDV-Driven CD4+ Lymphomas and Responding CD8+ T Cells

Lymphoid oncogenesis is a life threatening complication associated with a number of persistent viral infections (e.g. EBV and HTLV-1 in humans). With many of these infections it is difficult to study their natural history and the dynamics of tumor formation. Marek's Disease Virus (MDV) is a prevalent α-herpesvirus of poultry, inducing CD4+ TCRαβ+ T cell tumors in susceptible hosts. The high penetrance and temporal predictability of tumor induction raises issues related to the clonal structure of these lymphomas. Similarly, the clonality of responding CD8 T cells that infiltrate the tumor sites is unknown. Using TCRβ repertoire analysis tools, we demonstrated that MDV driven CD4+ T cell tumors were dominated by one to three large clones within an oligoclonal framework of smaller clones of CD4+ T cells. Individual birds had multiple tumor sites, some the result of metastasis (i.e. shared dominant clones) and others derived from distinct clones of transformed cells. The smaller oligoclonal CD4+ cells may represent an anti-tumor response, although on one occasion a low frequency clone was transformed and expanded after culture. Metastatic tumor clones were detected in the blood early during infection and dominated the circulating T cell repertoire, leading to MDV associated immune suppression. We also demonstrated that the tumor-infiltrating CD8+ T cell response was dominated by large oligoclonal expansions containing both “public” and “private” CDR3 sequences. The frequency of CD8+ T cell CDR3 sequences suggests initial stimulation during the early phases of infection. Collectively, our results indicate that MDV driven tumors are dominated by a highly restricted number of CD4+ clones. Moreover, the responding CD8+ T cell infiltrate is oligoclonal indicating recognition of a limited number of MDV antigens. These studies improve our understanding of the biology of MDV, an important poultry pathogen and a natural infection model of virus-induced tumor formation

Dietary fat and breast cancer risk revisited: a meta-analysis of the published literature

Animal experiments and human ecological studies suggest that dietary fat intake is associated with a risk of breast cancer, but individual-based studies have given contradictory results. We have carried out a meta-analysis of this association to include all papers published up to July 2003. Case-control and cohort studies that examined the association of dietary fat, or fat-containing foods, with risk of breast cancer were identified. A total of 45 risk estimates for total fat intake were obtained. Descriptive data from each study were extracted with an estimate of relative risk and its associated 95% confidence interval (CI), and were analysed using the random effects model of DerSimonian and Laird. The summary relative risk, comparing the highest and lowest levels of intake of total fat, was 1.13 (95% CI: 1.03-1.25). Cohort studies (N=14) had a summary relative risk of 1.11 (95% CI: 0.99-1.25) and case-control studies (N=31) had a relative risk of 1.14 (95% CI 0.99-1.32). Significant summary relative risks were also found for saturated fat (RR, 1.19; 95% CI: 1.06-1.35) and meat intake (RR, 1.17; 95% CI 1.06-1.29). Combined estimates of risk for total and saturated fat intake, and for meat intake, all indicate an association between higher intakes and an increased risk of breast cancer. Case-control and cohort studies gave similar results

Breast cancer in young women

Although uncommon, breast cancer in young women is worthy of special attention due to the unique and complex issues that are raised. This article reviews specific challenges associated with the care of younger breast cancer patients, which include fertility preservation, management of inherited breast cancer syndromes, maintenance of bone health, secondary prevention, and attention to psychosocial issues