Multiple Criteria Decision Analysis for HTA across four EU Member States: Piloting the Advance Value Framework.

Multiple Criteria Decision Analysis (MCDA) has emerged as a methodology for Health Technology Assessment (HTA). However, limited empirical evidence is available on its use by decision-makers; where available, it only comes from single-setting exercises, while cross-country comparative studies are unavailable. This study applies the Advance Value Framework (AVF), an MCDA methodology for HTA based on multi-attribute value theory, through a series of case studies with decision-makers in four countries, to explore its feasibility and compare decision-makers' value preferences and results. The AVF was applied in the evaluation of three drugs for metastatic, castrate resistant, prostate cancer (abiraterone, cabazitaxel and enzalutamide) in the post-chemotherapy indication. Decision conferences were organised in four European countries in collaboration with their HTA or health insurance organisations by involving relevant assessors and experts: Sweden (TLV), Andalusia/Spain (AETSA), Poland (AOTMiT) and Belgium (INAMI-RIZIV). Participants' value preferences, including performance scoring and criteria weighting, were elicited through a facilitated decision-analysis modelling approach using the MACBETH technique. Between 6 and 11 criteria were included in each jurisdiction's value model, allocated across four criteria domains; Therapeutic Benefit criteria consistently ranked first in relative importance across all countries. Consistent drug rankings were observed in all settings, with enzalutamide generating the highest overall weighted preference value (WPV) score, followed by abiraterone and cabazitaxel. Dividing drugs' overall WPV scores by their costs produced the lowest "cost per unit of value" for enzalutamide, followed by abiraterone and cabazitaxel. These results come in contrast with the actual country HTA recommendations and pricing decisions. Overall, although some differences in value preferences were observed between countries, drug rankings remained the same. The MCDA methodology employed could act as a decision support tool in HTA, due to the transparency in the construction of value preferences in a collaborative manner.

Intratumoural evolutionary landscape of high-risk prostate cancer: the PROGENY study of genomic and immune parameters.

BACKGROUND: Intratumoural heterogeneity (ITH) is well recognised in prostate cancer (PC), but its role in high-risk disease is uncertain. A prospective, single-arm, translational study using targeted multiregion prostate biopsies was carried out to study genomic and T-cell ITH in clinically high-risk PC aiming to identify drivers and potential therapeutic strategies. PATIENTS AND METHODS: Forty-nine men with elevated prostate-specific antigen and multiparametric-magnetic resonance imaging detected PC underwent image-guided multiregion transperineal biopsy. Seventy-nine tumour regions from 25 patients with PC underwent sequencing, analysis of mutations, copy number and neoepitopes combined with tumour infiltrating T-cell subset quantification. RESULTS: We demonstrated extensive somatic nucleotide variation and somatic copy number alteration heterogeneity in high-risk PC. Overall, the mutational burden was low (0.93/Megabase), but two patients had hypermutation, with loss of mismatch repair (MMR) proteins, MSH2 and MSH6. Somatic copy number alteration burden was higher in patients with metastatic hormone-naive PC (mHNPC) than in those with high-risk localised PC (hrlPC), independent of Gleason grade. Mutations were rarely ubiquitous and mutational frequencies were similar for mHNPC and hrlPC patients. Enrichment of focal 3q26.2 and 3q21.3, regions containing putative metastasis drivers, was seen in mHNPC patients. We found evidence of parallel evolution with three separate clones containing activating mutations of ß-catenin in a single patient. We demonstrated extensive intratumoural and intertumoural T-cell heterogeneity and high inflammatory infiltrate in the MMR-deficient (MMRD) patients and the patient with parallel evolution of ß-catenin. Analysis of all patients with activating Wnt/ß-catenin mutations demonstrated a low CD8+/FOXP3+ ratio, a potential surrogate marker of immune evasion. CONCLUSIONS: The PROGENY (PROstate cancer GENomic heterogeneitY) study provides a diagnostic platform suitable for studying tumour ITH. Genetic aberrations in clinically high-risk PC are associated with altered patterns of immune infiltrate in tumours. Activating mutations of Wnt/ß-catenin signalling pathway or MMRD could be considered as potential biomarkers for immunomodulation therapies. CLINICAL TRIALS.GOV IDENTIFIER: NCT02022371.

Targeting protein kinase C in sarcoma.

Protein kinase C (PKC) is a family of serine/threonine tyrosine kinases that regulate many cellular processes including division, proliferation, survival, anoikis and polarity. PKC is abundant in many human cancers and aberrant PKC signalling has been demonstrated in cancer models. On this basis, PKC has become an attractive target for small molecule inhibition within oncology drug development programmes. Sarcoma is a heterogeneous group of mesenchymal malignancies. Due to their relative insensitivity to conventional chemotherapies and the increasing recognition of the driving molecular events of sarcomagenesis, sarcoma provides an excellent platform to test novel therapeutics. In this review we provide a structure-function overview of the PKC family, the rationale for targeting these kinases in sarcoma and the state of play with regard to PKC inhibition in the clinic.

Experience in a UK cancer centre of weekly paclitaxel in the treatment of relapsed ovarian and primary peritoneal cancer.

OBJECTIVES: Weekly paclitaxel (WP) has been reported to have significant activity in patients with ovarian and primary peritoneal cancer patients while retaining a favorable toxicity profile. This study assessed the current usage of WP in routine clinical practice in a tertiary cancer center. METHODS: We conducted a retrospective audit in 53 patients with recurrent ovarian or primary peritoneal cancer treated with WP (80-100 mg/m(2)) over a 2-year period (Nov 2003-Nov 2005). Toxicity was assessed using Common Toxicity Criteria, and response was evaluated using radiological and CA-125 criteria. RESULTS: Patients had a median age of 69 (36-86) and previously received a median of 3 treatments (range 1-7). A median of 13 weekly doses of paclitaxel (range 1-39) were given. The response rate was 48% by radiological criteria and 69% by CA-125 assessment. Grade 3 toxicities were fatigue (13% of patients), peripheral neuropathy (11%) and neutropenia (8%) and there were no grade 4 toxicities. The median progression-free survival was 4. 8 months and median survival was 13. 5 months. There was no significant difference in efficacy between those 24 patients previously treated with taxanes (radiol. response 43%/CA-125 response 63%) and those 29 patients who had not received prior taxanes (radiol. response 52%/CA-125 response 76%). There was also no difference in efficacy for patients with platinum-free or treatment-free intervals of less than 6 months compared to 6 months or longer. CONCLUSIONS: WP is a well tolerated and active regimen in patients with pre-treated ovarian cancer and its use in recurrent disease is likely to increase. Further studies should aim to assess the importance of the "paclitaxel-free interval" in predicting response in relapsed disease, along similar lines as are now established for platinums.

Novel therapeutic agents in ovarian cancer.

AIMS: Epithelial ovarian cancer is responsible for 4% of all cancer deaths in women, and the five-year overall survival of patients with advanced disease is 30-40%. Treatment currently comprises a combination of surgery and chemotherapy with carboplatin and paclitaxel. The main reason for treatment failure is that the majority of patients present with advanced disease, and current drugs are unable to effect a cure even in chemosensitive patients. This article systematically reviews novel therapeutic strategies that have been evaluated in patients with ovarian cancer in the last 5 years. METHODS: Pubmed (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?DB=pubmed) and American Society of Clinical Oncology Annual conference abstracts were searched using the terms "(phase I OR phase II OR phase III OR phase 1 OR phase 2 OR phase 3) AND (ovary OR ovarian) AND (cancer OR carcinoma)" from January 2000 to May 2005 to identify studies for potential inclusion in this review. Reviews of novel therapies in ovarian cancer were also used to identify additional clinical trials. FINDINGS: A wide range of therapeutic strategies are currently being evaluated in ovarian cancer. These include novel cytotoxics, small molecule inhibitors, monoclonal antibodies, gene therapy and immuno-therapy strategies. The rationale for the development of these agents includes enhancement of efficacy by targeting novel biological pathways, re-sensitisation to existing drugs, simplification of drug administration and/or reduction of drug-toxicity. CONCLUSIONS: Current developments have the potential to result in substantial improvements in the outlook for women with ovarian cancer.

Variable use of endoscopic haemostasis in the management of bleeding peptic ulcers.

BACKGROUND: Randomised controlled trials (RCTs) have shown that endoscopic haemostasis is beneficial for patients with a bleeding peptic ulcer. The relevance of such data to management outside of RCTs is unclear. Therefore we examined management of patients with a bleeding peptic ulcer in a UK teaching hospital. METHODS: All patients who underwent upper gastrointestinal (UGI) endoscopy for bleeding peptic ulcer between 1997 and 1999 were identified from an endoscopy database and the clinical records reviewed retrospectively. RESULTS: A total of 872 patients underwent UGI endoscopy for presumed acute UGI haemorrhage; 179 (21%) had an endoscopic diagnosis of bleeding peptic ulcer. Seventy nine patients had a peptic ulcer with stigmata of recent haemorrhage (SRH) but only 61 (77%) of these patients received endoscopic haemostasis (77% adrenaline, 23% combination therapy). Re-bleeding occurred in 24 patients with SRH in whom transfusion requirement was the sole predictor of re-bleeding. The re-bleeding rate among patients who received adrenaline was 25% (n=12), compared with 57% (n=8) in the combination group and 31% (n=4) in those who did not receive endoscopic haemostasis. Patients who received combination endoscopic haemostasis had an increased incidence of active bleeding (p=0.007) and an increased transfusion requirement (p=0.002). Eleven of 20 patients who re-bled had repeat endoscopic haemostasis, with 45% eventually requiring surgery. CONCLUSIONS: Results of endoscopic management of bleeding peptic ulcers in the unit studied differ markedly from those published by specialised centres. The data reported here suggest that increased standardisation of endoscopic haemostasis is required, especially in units with provision for emergency "out-of-hours" endoscopy, performed by several individuals of different grades.