Wang W.,King's College London |
Wang W.,University of Edinburgh |
Hodkinson P.,Crosshouse Hospital |
Hodkinson P.,University of Edinburgh |
And 8 more authors.
Chest | Year: 2013
Background: Small cell lung carcinoma (SCLC) continues to have a poor prognosis, with a 2-year survival of < 20%. Studies have suggested that SCLC may affect the immune system to allow it to evade immunologic responses. We hypothesized that any such effect would be characterized by a decrease in the lymphoid cells associated with the tumor in biopsy specimens and that this might relate to patient outcome. Methods: Sixty-four SCLC biopsy specimens were immunohistochemically stained with anti-CD45 antibody to identify immune cells associated with the tumor. A mean CD45 count per high-power field for each case was obtained, and the results were correlated with age, sex, stage, performance status (PS), treatment with chemotherapy/radiotherapy, and overall survival. Results: The median CD45 count for all cases was taken as 40 (CD45 40). Kaplan-Meier plots demonstrated better survival for patients with a CD4540 > 40 (P < .009). No relationship between CD4540 and age, sex, stage, or treatment by chemotherapy or radiotherapy was identified. Although PS was a significant predictor of survival (P = .014), it did not correlate with CD4540. In patients with better Eastern Cooperative Oncology Group PS (≤ 2), the CD4540 demonstrated a highly significant survival advantage for those with CD45 40 > 40 (P < .0001). Conclusions: The data indicate that (1) simple immunohistochemical assessment of immune cell infiltrates in routinely processed and stained biopsy specimens of primary tumors can provide prognostic information in SCLC and (2) tumor-associated CD45+ cells in SCLC biopsy specimens may be a good clinical marker to identify patients with poor prognosis despite good PS. © 2013 American College of Chest Physicians.
Dickinson P.D.,Christie NHS Foundation Trust |
Malik J.,Edinburgh Cancer Center |
Mandall P.,Christie NHS Foundation Trust |
Swindell R.,Christie NHS Foundation Trust |
And 4 more authors.
BJU International | Year: 2014
Objective To report the outcomes of >1000 men with low-risk prostate cancer treated with low-dose-rate (LDR) brachytherapy at three large UK cancer centres. Patients and Methods A total of 1038 patients with low-risk prostate cancer (prostate-specific antigen [PSA] ≤10 ng/mL, Gleason score 6, ≤T2b disease) were treated with LDR iodine 125 (I-125) brachytherapy between 2002 and 2007. Patients were treated at three UK centres. PSA and clinical follow-up was performed at each centre. Biochemical recurrence-free survival was reported for the cohort. Results The median (range) PSA follow-up for the whole group was 5 years (4 months to 9 years). A total of 79 patients had biochemical failure, defined by a rise in PSA level: 16 patients fulfilled the ASTRO definition of biochemical failure, 25 patients fulfilled the Phoenix definition and 38 patients fulfilled both definitions. The 5-year biochemical relapse-free survival (bRFS) rate was 94.1% by the ASTRO definition and 94.2% by the Phoenix definition. The absence of neoadjuvant hormone therapy was predictive of inferior biochemical control as defined by the Phoenix definition (P = 0.033). Conclusions Our prospective multicentre series showed excellent bRFS with LDR I-125 brachytherapy for patients with low-risk prostate cancer. Further work is necessary to define the role of neoadjuvant androgen deprivation therapy in combination with brachytherapy. © 2013 The Authors. BJU International © 2013 BJU International.
Seymour M.T.,University of Leeds |
Brown S.R.,University of Leeds |
Middleton G.,University of Birmingham |
Maughan T.,University of Oxford |
And 17 more authors.
The Lancet Oncology | Year: 2013
Background: Therapeutic antibodies targeting EGFR have activity in advanced colorectal cancer, but results from clinical trials are inconsistent and the population in which most benefit is derived is uncertain. Our aim was to assess the addition of panitumumab to irinotecan in pretreated advanced colorectal cancer. Methods: In this open-label, randomised trial, we enrolled patients who had advanced colorectal cancer progressing after fluoropyrimidine treatment with or without oxaliplatin from 60 centres in the UK. From December, 2006 until June, 2008, molecularly unselected patients were recruited to a three-arm design including irinotecan (control), irinotecan plus ciclosporin, and irinotecan plus panitumumab (IrPan) groups. From June 10, 2008, in response to new data, the trial was amended to a prospectively stratified design, restricting panitumumab randomisation to patients with KRAS wild-type tumours; the results of the comparison between the irinotcan and IrPan groups are reported here. We used a computer-generated randomisation sequence (stratified by previous EGFR targeted therapy and then minimised by centre, WHO performance status, previous oxaliplatin, previous bevacizumab, previous dose modifications, and best previous response) to randomly allocate patients to either irinotecan or IrPan. Patients in both groups received 350 mg/m2 intravenous irinotecan every 3 weeks (300 mg/m2 if aged ≥70 years or a performance status of 2); patients in the IrPan group also received intravenous panitumumab 9 mg/kg every 3 weeks. The primary endpoint was overall survival in KRAS wild-type patients who had not received previous EGFR targeted therapy, analysed by intention to treat. Tumour DNA was pyrosequenced for KRASc.146, BRAF, NRAS, and PIK3CA mutations, and predefined molecular subgroups were analysed for interaction with the effect of panitumumab. This study is registered, number ISRCTN93248876. Results: Between Dec 4, 2006, and Aug 31, 2010, 1198 patients were enrolled, of whom 460 were included in the primary population of patients with KRASc.12-13,61 wild-type tumours and no previous EGFR targeted therapy. 230 patients were randomly allocated to irinotecan and 230 to IrPan. There was no difference in overall survival between groups (HR 1·01, 95% CI 0·83-1·23; p=0·91), but individuals in the IrPan group had longer progression-free survival (0·78, 0·64-0·95; p=0·015) and a greater number of responses (79 [34%] patients vs 27 [12%]; p<0·0001) than did individuals in the irinotecan group. Grade 3 or worse diarrhoea (64 [29%] of 219 patients vs 39 [18%] of 218 patients), skin toxicity (41 [19%] vs none), lethargy (45 % vs 24 [11%]), infection (42 [19%] vs 22 [10%]) and haematological toxicity (48 [22%] vs 27 [12%]) were reported more commonly in the IrPan group than in the irinotecan group. We recorded five treatment-related deaths, two in the IrPan group and three in the irinotecan group. Interpretation: Adding panitumumab to irinotecan did not improve the overall survival of patients with wild-type KRAS tumours. Further refinement of molecular selection is needed for substantial benefits to be derived from EGFR targeting agents. Funding: Cancer Research UK, Amgen Inc. © 2013 Elsevier Ltd.
Hacking B.,Edinburgh Cancer Center |
Wallace L.,Coventry University |
Scott S.,Edinburgh Cancer Center |
Kosmala-Anderson J.,Coventry University |
And 2 more authors.
Psycho-Oncology | Year: 2013
Objective Does decision navigation (DN) increase prostate cancer patients' confidence and certainty in treatment decisions, while reducing regret associated with the decisions made? Methods Two hundred eighty-nine newly diagnosed prostate cancer patients were eligible. 123 consented and were randomised to usual care (n = 60) or navigation (n = 63). The intervention involved a 'navigator' guiding the patient in creating a personal question list for a consultation and providing a CD and typed summary of the consultation to patients, the general practitioner and physician. The primary outcome was decisional self efficacy. Secondary outcomes included decisional conflict (DCS) and decisional regret (RS). Measures of mood (Hospital Anxiety and Depression Scale) and adjustment (Mental Adjustment to Cancer Scale) were included to detect potential adverse effects of the intervention. Results ANOVA showed a main effect for the group (F = 7.161, df 1, p = 0.009). Post hoc comparisons showed significantly higher decisional self efficacy in the navigated patients post-consultation and 6 months later. Decisional conflict was lower for navigated patients initially (t = 2.005, df = 105, p = 0.047), not at follow-up (t = 1.969, df = 109, p = 0.052). Regret scores were significantly lower in the navigation group compared to the controls 6 months later (t = -2.130, df = 100, p = 0.036). There was no impact of the intervention on mood or adjustment. Conclusion Compared to control patients, navigated patients were more confident in making decisions about cancer treatment, were more certain they had made the right decision after the consultation and had less regret about their decision 6 months later. Decision navigation was feasible, acceptable and effective for newly diagnosed prostate cancer patients in Scotland. Copyright © 2012 John Wiley & Sons, Ltd.
Clinical outcomes in patients with castrate-refractory prostate cancer (CRPC) metastatic to bone randomized in the factorial TRAPEZE trial to docetaxel (D) with strontium-89 (Sr89), zoledronic acid (ZA), neither, or both (ISRCTN 12808747)
PubMed | The Christie Hospital NHS Foundation Trust, University of Liverpool, Derby Royal Hospital, Queen Elizabeth Hospital and 10 more.
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2017
LBA5000 Background: Bony metastatic CRPC has a poor prognosis and high morbidity. TRAPEZE is a factorial RCT using three agents, D, ZA, and Sr89. All have palliative benefits and are used in bony metastatic CRPC to control bone symptoms and (for D) to prolong survival. ZA was approved on the basis of reducing skeletal related events (SRE). Sr89 was approved to control pain from metastases and to reduce the need for subsequent bone treatments. ZA is commonly combined with D in practice but evidence that the combination is effective is lacking and costs considerable. Sr89 is generally used as a palliative therapy in patients unfit for chemotherapy. Phase II analysis confirmed the safety and feasibility of combining these agents. TRAPEZE aimed to determine clinical and cost-effectiveness scheduling.Patients were randomised to receive 6 cycles of D plus prednisolone: alone; with ZA; with a single dose of Sr89 after cycle 6 or both. Primary outcomes were clinical progression-free survival (CPFS: pain progression, SRE or death) and cost-effectiveness. Secondary outcomes were SRE free interval (SREFI); total SREs, and overall survival (OS). The log rank test and Cox regression modelling were used to determine clinical effectiveness.TRAPEZE randomised 757 patients; median age 68.7 yrs; ECOG 0: 40% 1: 52% 2: 8%; prior RT 45%; median PSA 144 (IQR 51, 354). Provisional stratified log rank analysis of CPFS did not reach statistical significance for either agent (Sr89 p=0.11, ZA p=0.45). Cox regression analysis adjusted for all stratification variables showed benefit of Sr89 on CPFS (HR=0.845; 95%CI 0.72, 0.99, p=0.036) and confirmed no effect of ZA (p=0.46). ZA did show a significant effect on SREFI (HR=0.76; 95%CI 0.63, 0.93, p=0.008). There was no effect of either agent on overall survival (Sr89 p=0.74, ZA p=0.91).Sr89 after six cycles of docetaxel improved CPFS but not OS. ZA did not improve CPFS or OS but did significantly improve median SREFI, mostly post progression, suggesting a role as post chemotherapy maintenance therapy. Further health economic and QoL analyses are pending.12808747.
Bedi C.,Edinburgh Cancer Center |
Kron T.,Peter MacCallum Cancer Center |
Kron T.,RMIT University |
Willis D.,Peter MacCallum Cancer Center |
And 4 more authors.
Clinical Oncology | Year: 2011
Aims: The target volume for breast radiotherapy after conservative surgery for breast cancer may be affected by breathing motion. We investigated differences between conventional and four-dimensional computed tomography-based treatment planning and whether gating could improve dose volume parameters. Materials and methods: Ten patients with left-sided breast cancer and surgical clips at the excision site had conventional treatment planning computed tomography and four-dimensional computed tomography. Treatment plans using two tangential beams (6. MV X-rays) were optimised for target coverage and homogeneity using a field in field technique for the three-dimensional scan. This plan was applied directly to four-dimensional datasets representing individual phases of the breathing cycle and combinations thereof (average and maximum intensity projection). Optimised plans were generated for the maximum inhalation scan to study what could potentially be achieved in gated radiotherapy. Results: Four-dimensional computed tomography with effective doses of around 10 mSv proved to be adequate for treatment planning in all patients. The average motion of the surgical clips was 3.7. mm (range 1.7-6.5. mm), which was similar to the movement of the chest wall. With a margin of 7 mm for the whole breast to planning target volume, conventional three-dimensional computed tomography-based planning was found to adequately cover the target as seen on four-dimensional computed tomography without significant differences in normal tissue sparing. Improved sparing of the heart and lung could only be achieved by reducing the posterior margin of the target volume, which may be justified if four-dimensional computed tomography is used to determine the target and its motion. Conclusion: No significant benefit has been shown for the use of four-dimensional computed tomography-based planning if motion management is not implemented concurrently with a reduced posterior margin between clinical and planning target volumes. © 2011 The Royal College of Radiologists.
Thekkumpurath P.,University of Edinburgh |
Walker J.,University of Edinburgh |
Butcher I.,University of Edinburgh |
Hodges L.,University of Edinburgh |
And 6 more authors.
Cancer | Year: 2011
BACKGROUND: Systematic screening for depression has been recommended for patients who have medical conditions like cancer. The 9-item Patient Health Questionnaire (PHQ-9) is becoming widely used, but its diagnostic accuracy has not yet been tested in a cancer patient population. In this article, the authors report on the performance of the PHQ-9 as a screening instrument for major depressive disorder (MDD) in patients with cancer. METHODS: Data obtained from a depression screening service for patients who were attending clinics of a Regional Cancer Centre in Edinburgh, United Kingdom were used. Patients had completed both the PHQ-9 and a 2-stage procedure to identify cases of MDD. Performance of the PHQ-9 in identifying cases of MDD was determined using receiver operating characteristic (ROC) analysis. RESULTS: Data were available on 4264 patients. When scored as a continuous measure, the PHQ-9 performed well with an area under the ROC curve of 0.94 (95% confidence interval [CI], 0.93-0.95). A cutoff score of a≥8 provided a sensitivity of 93% (95% CI, 89%-95%), a specificity of 81% (95% CI, 80%-82%), a positive predictive value (PPV) of 25%, and a negative predictive value (NPV) of 99% and could be considered optimum in a screening context. The PHQ-9 did not perform as well when it was scored using an algorithm with a sensitivity of 56% (95% CI, 55%-57%), a specificity of 96% (95% CI, 95%-97%), a PPV of 52%, and an NPV of 97%. CONCLUSIONS: The PHQ-9 scored as a continuous measure with a cutoff score of a≥8 performed well in identifying MDD in cancer patients and should be considered as a screening instrument in this population. © 2010 American Cancer Society.
Price A.,Edinburgh Cancer Center
Oncologist | Year: 2011
Objective. A review of the evidence supporting the use of radiotherapy in patients with mesothelioma was performed. Methods. Relevant publications were searched for on Medline. Results. In aMedline search on radiotherapy and mesothelioma, 611 hits were obtained. A limited number of prospective phase II trials of radiotherapy as part of trimodality protocols for early disease and in the palliation of pain were found, along with three small randomized controlled trials of port-site prophylaxis. Conclusion. No randomized data exist to support the use of radiotherapy after radical surgery, although there are a large number of publications describing its use as an integral part of therapy, including seven phase II studies. One ongoing trial is randomizing patients to radiotherapy or not after extrapleural pneumonectomy. None of these studies provided any assessment of radiotherapy independent of the other modalities investigated, nor did any formally assess intensity-modulated radiotherapy. There have been several reports of excessive toxicity with this technique, and its use should be limited to phase I studies until the basis of this toxicity is better understood. Three trials have looked at port-site prophylaxis, one supporting its use and two showing no evidence of benefit.Twostudies addressed pain control prospectively, one showing definite but short-lived benefits. Implications. Radiotherapy is widely used in treating mesothelioma with little supporting evidence. More randomized trials are required to justify this use in all three common settings for its use. © AlphaMed Press.
Quintayo M.A.,University of Edinburgh |
Quintayo M.A.,Ontario Cancer Institute |
Munro A.F.,University of Edinburgh |
Thomas J.,Edinburgh Cancer Center |
And 7 more authors.
Breast Cancer Research and Treatment | Year: 2012
Glycogen synthase kinase 3β (GSK3β) is phosphorylated and inactivated by the phosphoinositide 3 kinase PI3K/Akt pathway. Activation of Akt phosphorylates GSK3β preventing phosphorylation of cyclin D1 which leads to accumulation and nuclear localisation of cyclin D1, activation of CDK4/6 and cell cycle progression. The CCND1 gene found at chromosome 11q13 has been shown to be amplified in approximately 15 % of breast cancers. Cyclin D1, the product of the CCND1 gene, is one of the most commonly overexpressed proteins in breast cancer. Protein expression for GSK3β, phosphorylated-GSK3β (p-GSK3β), cyclin D1 and gene expression of CCND1 were examined in tissue microarrays of 1,686 patients from the Edinburgh Breast Conservation Series. High GSK3β expression was associated with reduced distant relapse-free survival (DRFS), while no association between p-GSK3β and breast cancer-specific survival was seen. CCND1 amplification is also associated with poor DRFS. On the contrary, cyclin D1 overexpression is associated with an increase in DRFS. Multivariate analysis was performed. We suggest that analysis of both GSK3β and cyclin D1 expressions can be considered as a marker of good prognosis in early breast cancer. © 2012 Springer Science+Business Media, LLC.
PubMed | Western General Hospital and Edinburgh Cancer Center
Type: Journal Article | Journal: Clinical oncology (Royal College of Radiologists (Great Britain)) | Year: 2015
To analyse our 5 and 10 year prostate brachytherapy outcome data and to assess the impact of PSA nadir on relapse free survival and whether an alternative definition of PSA relapse could detect men destined to fail by the Phoenix definition at an earlier time point.474 men were treated over a 10 year period between 20012 and 2011 and divided into 2 five year cohorts for the purpose of the analysis.The risk of relapse is strongly predicted by post treat prostate-specific antigen (PSA) nadir. After 3 years post-treatment, PSA nadir plus 0.4 ng/ml identified men at risk of relapse 17 months earlier than the Phoenix definition.The Phoenix definition of nadir plus 2.0 ng/ml does not allow the early identification of men destined to relapse. The initiation of salavage therapy at the earliest opportunity could potentially affect subsequent survival and an outline randomised controlled trial proposal is presented.