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PubMed | University of Southampton, Velindre Hospital, University of Bristol, Glan Clwyd Hospital and 7 more.
Type: Clinical Trial, Phase II | Journal: British journal of cancer | Year: 2015

Limited data describe patient-reported outcomes (PROs) of localised oesophageal cancer treated with definitive chemoradiotherapy(CRT). The phase 2/3 SCOPE-1 trial assessed the effectiveness of CRTcetuximab. The trial for the first time provided an opportunity to describe PROs from a multi-centre group of patients treated with CRT that are presented here.Patients undergoing CRTcetuximab within the SCOPE-1 trial (258 patients from 36 UK centres) completed generic-, disease- and treatment-specific health-related quality of life (HRQL) questionnaires (EORTC QLQ-C30, QLQ-OES18, Dermatology Life-Quality Index (DLQI)) at baseline and at 7, 13, 24, 52 and 104 weeks. Mean EORTC functional scale scores (>15 point change significant), DLQI scores (>4 point change significant) and proportions of patients (>15% significant) with minimal or severe symptoms are presented.Questionnaire response rates were good. At baseline, EORTC functional scores were high (>75%) and few symptoms were reported except for severe problems with fatigue, insomnia and eating-related symptoms (e.g., appetite loss, dysphagia, dry mouth) in both groups(>15%). Functional aspects of health deteriorated and symptoms increased with treatment and by week 13 global quality of life, physical, role and social function significantly deteriorated and more problems with fatigue, dyspnoea, appetite loss and trouble with taste were reported. Recovery occurred by 6 months (except severe fatigue and insomnia in >15% of patients) and maintained at follow-up with no differences between groups.CRT for localised oesophageal cancer has a significant detrimental impact on many aspects of HRQL; however, recovery is achieved by 6 months and maintained with the exception of persisting problems with severe fatigue and insomnia. The data suggest that the HRQL recovery after definitive CRT is quicker, and there is little lasting deficit compared with treatment including surgery. These data need to be compared with HRQL data from studies evaluating treatments including surgery for oesophageal cancer.


Luchtenborg M.,King's College London | Riaz S.P.,King's College London | Coupland V.H.,King's College London | Moller H.,King's College London | And 6 more authors.
Journal of Clinical Oncology | Year: 2013

Purpose Studies have reported an association between hospital volume and survival for non-small-cell lung cancer (NSCLC). We explored this association in England, accounting for case mix and propensity to resect. Methods We analyzed data on 134,293 patients with NSCLC diagnosed in England between 2004 and 2008, of whom 12,862 (9.6%) underwent surgical resection. Hospital volume was defined according to number of patients with resected lung cancer in each hospital in each year of diagnosis. We calculated hazard ratios (HRs) for death in three predefined periods according to hospital volume, sex, age, socioeconomic deprivation, comorbidity, and propensity to resect. Results There was increased survival in hospitals performing > 150 surgical resections compared with those carrying out < 70 (HR, 0.78; 95% CI, 0.67 to 0.90; Ptrend < .01). The association between hospital volume and survival was present in all three periods of follow-up, but the magnitude of association was greatest in the early postoperative period. Conclusion High-volume hospitals have higher resection rates and perform surgery among patients who are older, have lower socioeconomic status, and have more comorbidities; despite this, they achieve better survival, most notably in the early postoperative period. © 2013 by American Society of Clinical Oncology.


Luchtenborg M.,King's College London | Luchtenborg M.,Public Health England | Riaz S.P.,Public Health England | Lim E.,Royal Brompton Hospital | And 11 more authors.
Thorax | Year: 2014

Introduction: Chemotherapy or chemoradiotherapy is the recommended treatment for small cell lung cancer (SCLC), except in stage I disease where clinical guidelines state there may be a role for surgery based on favourable outcomes in case series. Evidence supporting adjuvant chemotherapy in resected SCLC is limited but this is widely offered. Methods: Data on 359 873 patients who were diagnosed with a first primary lung cancer in England between 1998 and 2009 were grouped according to histology (SCLC or non-SCLC (NSCLC)) and whether they underwent a surgical resection. We explored their survival using Kaplan-Meier analysis and Cox regression, adjusting for age, sex, comorbidity and socioeconomic status. Results: The survival of 465 patients with resected SCLC was lower than patients with resected NSCLC (5-year survival 31% and 45%, respectively), but much higher than patients of either group who were not resected (3%). The difference between resected SCLC and NSCLC diminished with time after surgery. Survival was superior for the subgroup of 198 'elective' SCLC cases where the diagnosis was most likely known before resection than for the subgroup of 267 'incidental' cases where the SCLC diagnosis was likely to have been made after resection. Conclusions: These data serve as a natural experiment testing the survival after surgical management of SCLC according to NSCLC principles. Patients with SCLC treated surgically for early stage disease may have survival outcomes that approach those of NSCLC, supporting the emerging clinical practice of offering surgical resection to selected patients with SCLC.


Langley R.E.,MRC Clinical Trials Unit | Stephens R.J.,MRC Clinical Trials Unit | Nankivell M.,MRC Clinical Trials Unit | Pugh C.,MRC Clinical Trials Unit | And 7 more authors.
Clinical Oncology | Year: 2013

Aims: Over 30% of patients with non-small cell lung cancer (NSCLC) develop brain metastases. If inoperable, optimal supportive care (OSC), including steroids, and whole brain radiotherapy (WBRT) are generally considered to be standard care, although there is no randomised evidence demonstrating that the addition of WBRT to OSC improves survival or quality of life. Materials and methods: QUARTZ is a randomised, non-inferiority, phase III trial comparing OSC + WBRT versus OSC in patients with inoperable brain metastases from NSCLC. The primary outcome measure is quality-adjusted life years (QALYs). QUARTZ was threatened with both loss of funding and early closure due to poor accrual. A lack of preliminary randomised data supporting the trial's hypotheses was thought to underlie the poor accrual, so, with no knowledge of the data, the independent trial steering committee agreed to the unusual step of releasing interim data. Results: Between March 2007 and April 2010, 151 (of the planned 534) patients were randomised (75 OSC + WBRT, 76 OSC). Participants' baseline demographics included median age 67 years (interquartile range 62-73), 60% male, 50% with a Karnofsky performance status <70; steroid usage was similar in the two groups; 64/75 (85%) received WBRT (20 Gy in five fractions). Median survival was: OSC + WBRT 49 days (95% confidence interval 39-61), OSC 51 days (95% confidence interval 27-57) - hazard ratio 1.11 (95% confidence interval 0.80-1.53) in favour of WBRT. Quality of life assessed using EQ-5D showed no evidence of a difference. The estimated mean QALYs was: OSC + WBRT 31 days and OSC 30 days, difference -1 day (95% confidence interval -12.0 to +13.2 days). Conclusion: These interim data indicate no early evidence of detriment to quality of life, overall survival or QALYs for patients allocated to OSC alone. They provide key information for discussing the trial with patients and strengthen the argument for continuing QUARTZ to definitively answer this important clinical question. © 2012 The Royal College of Radiologists.


Agarwal V.,University of Hull | Agarwal V.,Queens Center for Oncology and Haematology | Hodgkinson V.C.,University of Hull | Eagle G.L.,University of Hull | And 4 more authors.
International Journal of Oncology | Year: 2013

We have previously shown that specific COX-2 inhibitors, including DuP 697, have anti-proliferative effects on mesothelioma cells and potentiate the cytotoxicity of pemetrexed. Here, we used a novel proteomic approach to explore the mechanism of action of this agent. COX-2-positive cell lines MSTO-211H (mesothelioma) and A549 (lung cancer) were exposed to DuP 697 for 72 h. Drug carrier only was added to control cells. Extracted proteins from treated and control cells were analysed using a comparative proteomic platform. Differentially expressed proteins, identified by the Panorama Xpress Profiler725 antibody microarray were submitted to Ingenuity Pathway Analysis. A total of 32 unique differentially expressed proteins were identified with a significant (>1.8-fold) difference in expression between treated and untreated cells in at least one cell line. Five molecules, BCL2L1 (Bcl-xL), BID, CHUK (IKK), FASLG and RAF1, were mapped to the Apoptosis Signaling pathway following Ingenuity Pathway Analysis. BCL2L1 (Bcl-xL) and BID were analysed using immunoblotting and differential expression was confirmed. Proteomic (antibody microarray) analysis suggests that the mechanism of action of DuP 697 may be exerted via the induction of apoptosis. The antibody microarray platform can be utilised to explore the molecular mechanism of action of novel anticancer agents.


Agarwal V.,University of Hull | Agarwal V.,Castle Hill Hospital | Agarwal V.,Queens Center for Oncology and Haematology | Campbell A.,University of Hull | And 6 more authors.
Tumor Biology | Year: 2013

Malignant pleural mesothelioma is associated with poor prognosis and despite recent advances in chemotherapy, the median survival is still approximately 12 months. Loss of phosphatase and tensin homolog (PTEN) protein expression may lead to constitutive activation of AKT resulting in cell survival and proliferation. Small studies reported that PTEN protein expression is rarely lost in mesothelioma whilst a larger study demonstrated prognostic significance of PTEN protein expression status with absence in 62 % of cases. We aimed to analyse PTEN protein expression in mesothelioma. Immunohistochemical analysis was performed in 86 archival mesothelioma samples to determine the PTEN protein expression status and statistical analysis was performed to identify any prognostic significance. Mesothelial cells in normal pleura demonstrated positive staining for PTEN protein and served as a positive reference. For mesothelioma samples, the expression of PTEN protein was scored as 0 (negative), 1 (intensity less than that of positive normal pleura reference slide) and 2 (intensity equal to or greater than positive normal pleura reference slide). A total of 23/86 (26.7 %) scored 0, 23/86 (26.7 %) scored 1 and 40/86 (46.5 %) scored 2 for PTEN expression. Univariate analysis demonstrated that lack of PTEN expression was not associated with survival. PTEN protein expression was undetectable in 26.7 % of mesothelioma samples; however, no prognostic significance was identified. Absence of PTEN protein may result in activation of the PI3K/AKT/MTOR pathway. Targeting this pathway with inhibitors further downstream of PTEN may provide a potential therapeutic target in selected patients. © 2012 International Society of Oncology and BioMarkers (ISOBM).


ELFadl D.,University of Hull | ELFadl D.,Academic Surgical Unit | Hodgkinson V.C.,University of Hull | Long E.D.,Hull and East Yorkshire NHS Trust | And 5 more authors.
Breast | Year: 2011

Breast conserving therapy is a currently accepted method for managing patients with early stage breast cancer. However, approximately 7% of patients may develop loco-regional tumour recurrence within 5 years. We previously reported that expression of the 26S proteasome may be associated with radio-resistance. Here we aimed to analyse the 26S proteasome in a pilot series of early breast cancers and correlate the findings with loco-regional recurrence. Fourteen patients with early breast cancer who developed loco-regional recurrence within 4 years of completing breast conserving therapy were selected according to strict criteria and compared with those from 14 patients who were disease-free at 10 years. Decreased expression of the 26S proteasome was significantly associated with radio-resistance, manifested as the development of a loco-regional recurrence within 4 years of breast conserving therapy (p = 0.018). This small pilot study provides further suggestion that the 26S proteasome may be associated with response to radiotherapy. © 2011 Elsevier Ltd.


Hodgkinson V.C.,University of Hull | ELFadl D.,University of Hull | ELFadl D.,Academic Surgical Unit | Drew P.J.,University of Hull | And 3 more authors.
Journal of Proteomics | Year: 2011

Antibody microarrays are powerful new tools in the field of comparative proteomics. The success of the biomarker discovery pipeline relies on the quality of data generated in the discovery phase and careful selection of proteins for the verification phase. Recent meta-analyses found a number of repeatedly identified differentially expressed proteins (RIDEPs) from mass spectrometry-based proteomics research in a range of species. We aimed to assess RIDEPs based on antibody microarray data-sets. A total of 13 independent experiments encompassing a range of oncology-related research on human tissue, cells or cell lines from 5 distinct sample groups were performed utilising a commercial 725 antibody microarray platform (Panorama XPRESS Profiler725; Sigma-Aldrich). Analysis of all microarray slides was carried out by the same individual to reduce inter-observer variability. Fold changes of ≥ 1.8 were considered significant. A total of 13 RIDEPs were seen, each appearing in at least 4/13 (30%) antibody microarray analyses from at least 2 out of 5 experimental sample groups. The phenomenon of RIDEPs may exist in antibody microarray proteomics and we report a preliminary list of 13 RIDEPs from the XPRESS Profiler725 platform. This information will be useful when interpreting experimental data and considering which DEPs should be prioritised for verification. © 2011 Elsevier B.V.


Hodgkinson V.C.,University of Hull | Agarwal V.,University of Hull | Agarwal V.,Queens Center for Oncology and Haematology | ELFadl D.,University of Hull | And 10 more authors.
Journal of Proteomics | Year: 2012

Neoadjuvant chemotherapy is used to treat oestrogen receptor-positive breast cancer however chemo-resistance is a major obstacle in this molecular subtype. The ability to predict tumour response would allow chemotherapy administration to be directed towards patients who would most benefit, thus maximising treatment efficacy. We aimed to identify protein biomarkers associated with response to neoadjuvant chemotherapy, in a pilot study using comparative 2-DE MALDI TOF/TOF MS proteomic analysis of breast tumour samples. A total of 3 comparative proteomic experiments were performed, comparing protein expression between chemotherapy-sensitive and chemotherapy-resistant oestrogen receptor-positive invasive ductal carcinoma tissue samples. This identified a list of 132 unique proteins that were significantly differentially expressed (≥ 2 fold) in chemotherapy resistant samples, 57 of which were identified in at least two experiments. Ingenuity® Pathway Analysis was used to map the 57 DEPs onto canonical signalling pathways. We implicate several isoforms of 14-3-3 family proteins (theta/tau, gamma, epsilon, beta/alpha and zeta/delta), which have previously been associated with chemotherapy resistance in breast cancer. Extensive clinical validation is now required to fully assess the role of these proteins as putative markers of chemotherapy response in luminal breast cancer subtypes. © 2012 Elsevier B.V..


Agarwal V.,University of Hull | Agarwal V.,Queens Center for Oncology and Haematology | Lind M.J.,University of Hull | Lind M.J.,Queens Center for Oncology and Haematology | Cawkwell L.,University of Hull
Cancer Treatment Reviews | Year: 2011

The median survival for patients with malignant pleural mesothelioma remains extremely poor and there is a need for the development of more effective treatment modalities. The epidermal growth factor receptor is frequently over-expressed in malignant pleural mesothelioma samples and therefore may be a potential therapeutic target. Targeted EGFR therapy has been successful in non-small cell lung cancer using small molecule tyrosine kinase inhibitors and in colorectal cancer using monoclonal anti-EGFR antibodies. However, phase II clinical trials based on EGFR tyrosine kinase inhibitor therapy have so far not shown promise in mesothelioma. This review includes a background to targeted EGFR treatment strategies, explores putative therapy resistance mechanisms, including the role of predictive biomarkers, and describes the current status of targeted EGFR therapeutic strategies for mesothelioma patients. © 2010 Elsevier Ltd.

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