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European journal of cardio-thoracic surgery: official journal of the European Association for Cardio-thoracic Surgery 01/2012; · 2.40 Impact Factor
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Judith M Bliss,
Gill Coombes,
Liz Darlison,
John Edwards,
James Entwisle,
Lucy S Kilburn,
David Landau,
Loic Lang-Lazdunski,
Mary O'Brien,
Ken O'Byrne,
Julian Peto,
Suresh Senan,
Michael Snee,
James Spicer, Carol Tan,
Gill Thomas,
Tom Treasure,
David Waller
The lancet oncology 11/2011; 12(12):1094-5. · 14.47 Impact Factor
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Tom Treasure,
Loic Lang-Lazdunski,
David Waller,
Judith M Bliss, Carol Tan,
James Entwisle,
Michael Snee,
Mary O'Brien,
Gill Thomas,
Suresh Senan,
Ken O'Byrne,
Lucy S Kilburn,
James Spicer,
David Landau,
John Edwards,
Gill Coombes,
Liz Darlison,
Julian Peto
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ABSTRACT: The effects of extra-pleural pneumonectomy (EPP) on survival and quality of life in patients with malignant pleural mesothelioma have, to our knowledge, not been assessed in a randomised trial. We aimed to assess the clinical outcomes of patients who were randomly assigned to EPP or no EPP in the context of trimodal therapy in the Mesothelioma and Radical Surgery (MARS) feasibility study.
MARS was a multicentre randomised controlled trial in 12 UK hospitals. Patients aged 18 years or older who had pathologically confirmed mesothelioma and were deemed fit enough to undergo trimodal therapy were included. In a prerandomisation registration phase, all patients underwent induction platinum-based chemotherapy followed by clinical review. After further consent, patients were randomly assigned (1:1) to EPP followed by postoperative hemithorax irradiation or to no EPP. Randomisation was done centrally with computer-generated permuted blocks stratified by surgical centre. The main endpoints were feasibility of randomly assigning 50 patients in 1 year (results detailed in another report), proportion randomised who received treatment, proportion eligible (registered) who proceeded to randomisation, perioperative mortality, and quality of life. Patients and investigators were not masked to treatment allocation. This is the principal report of the MARS study; all patients have been recruited. Analyses were by intention to treat. This trial is registered, number ISRCTN95583524.
Between Oct 1, 2005, and Nov 3, 2008, 112 patients were registered and 50 were subsequently randomly assigned: 24 to EPP and 26 to no EPP. The main reasons for not proceeding to randomisation were disease progression (33 patients), inoperability (five patients), and patient choice (19 patients). EPP was completed satisfactorily in 16 of 24 patients assigned to EPP; in five patients EPP was not started and in three patients it was abandoned. Two patients in the EPP group died within 30 days and a further patient died without leaving hospital. One patient in the no EPP group died perioperatively after receiving EPP off trial in a non-MARS centre. The hazard ratio [HR] for overall survival between the EPP and no EPP groups was 1·90 (95% CI 0·92-3·93; exact p=0·082), and after adjustment for sex, histological subtype, stage, and age at randomisation the HR was 2·75 (1·21-6·26; p=0·016). Median survival was 14·4 months (5·3-18·7) for the EPP group and 19·5 months (13·4 to time not yet reached) for the no EPP group. Of the 49 randomly assigned patients who consented to quality of life assessment (EPP n=23; no EPP n=26), 12 patients in the EPP group and 19 in the no EPP group completed the quality of life questionnaires. Although median quality of life scores were lower in the EPP group than the no EPP group, no significant differences between groups were reported in the quality of life analyses. There were ten serious adverse events reported in the EPP group and two in the no EPP group.
In view of the high morbidity associated with EPP in this trial and in other non-randomised studies a larger study is not feasible. These data, although limited, suggest that radical surgery in the form of EPP within trimodal therapy offers no benefit and possibly harms patients.
Cancer Research UK (CRUK/04/003), the June Hancock Mesothelioma Research Fund, and Guy's and St Thomas' NHS Foundation Trust.
The lancet oncology 06/2011; 12(8):763-72. · 14.47 Impact Factor
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ABSTRACT: There is a resurgence of interest in lung-sparing extirpative surgery for malignant pleural mesothelioma with recent reports of better survival and fewer adverse consequences than with extrapleural pneumonectomy. However, these operations are not well-characterized and to offer evidence-based clinical recommendations and to plan future trials a summary of what is already known is required.
A formal literature search was performed and all recovered titles were sequentially sifted by title, abstract and full-text reading according to prespecified criteria. Papers were selected if they contained data relevant to the area of enquiry. Quantitative synthesis and textual analysis, appropriate to the material, were performed.
Follow-up studies of patients undergoing surgery for malignant pleural mesothelioma in specialist thoracic or cardiothoracic units.
Among the operated patients described in these papers, a total of 1270 patients had undergone lung-sparing surgery for mesothelioma.
There were no randomized trials or other forms of controlled studies. From 464 titles, 26 papers contained sufficient data on 1270 patients to be included in the systematic review. Operative descriptions for all series were extracted and tabulated and variation was found in the nature of surgery within and between series, and the degree of detail with which it was described. There was more operative detail in recent papers. All available numerical data were extracted, tabulated and summarized using quantitative methods. The average survival at 1, 2, 3, 4 and 5 years was 51%, 26%, 16%, 11% and 9%, respectively. There were no data on patients' performance status, symptomatic change, or other patient reported outcomes.
In the absence of any form of control data, no conclusions can be drawn concerning survival differences or symptomatic benefits attributable to surgery. As mesothelioma surgery is restricted to a selected minority of patients who often have multiple therapies, future research will require controlled studies with explicit definitions of the clinical and surgical intent.
Journal of the Royal Society of Medicine 02/2011; 104(2):69-80. · 1.41 Impact Factor
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ABSTRACT: Prolonged alveolar air leak is the most common complication after pulmonary surgery. We conducted an investigator-led randomized trial to evaluate the effectiveness of CoSeal® surgical sealant (Cohesion Technologies Inc.; manufactured and distributed by Baxter Healthcare) for the closure of alveolar air leak after anatomical pulmonary resection.
Patients undergoing primary open lobectomy, bilobectomy, or sublobar resection with a demonstrable air leak on intra-operative testing were randomized to either standard care or standard care plus application of CoSeal® surgical sealant to areas of air leak. A second application of CoSeal® was used in the treatment group if air leak persisted. Patients were allocated at the point of entry to the trial by unbiased allocation with minimization to ensure balance between the two arms with respect to age, sex, surgeon, number of segments resected, preoperative forced expiratory volume in 1s (FEV₁), and grade of air leak. Kaplan-Meier analysis of air-leak duration and a log rank test were performed on an intention-to-treat basis, with observations censored at death, transfer to the intensive care unit, or discharge.
Of the 200 patients, who entered the trial over a 24-month period, 121 with demonstrable intra-operative air leak were randomly allocated to the two groups. Data were missing for one patient in the CoSeal® group. In 57%, the air leak was stopped at the first application; a quarter continued to leak after the second. At 24h, there was no difference in air leak and fewer patients in the control group were leaking at 48 h postoperatively. By log rank test, the difference was not significant (p=0.09).
Patients treated with CoSeal® in this study had, as a group, a longer duration of air leak and hence we cannot recommend its routine use.
European journal of cardio-thoracic surgery: official journal of the European Association for Cardio-thoracic Surgery 01/2011; 40(2):304-8. · 2.40 Impact Factor
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ABSTRACT: To investigate the role of 18-fluorodeoxyglucose positron emission tomography-computed tomography (18-FDG-PET-CT) in the surveillance of patients after multimodality treatment of malignant pleural mesothelioma.
Retrospective study of patients who had chemotherapy, radical surgery, extrapleural pneumonectomy or pleurectomy/decortication, and radiotherapy for mesothelioma in our unit. PET-CT was performed after multimodality therapy to evaluate response to treatment or when disease recurrence was suspected. 18-FDG-PET scans were acquired from skull base to upper thigh with low-dose CT scans for attenuation correction and image fusion.
Forty-four patients had extrapleural pneumonectomy (21) or pleurectomy/decortication (23) between January 2004 and July 2008. Twenty-five patients had PET-CT performed after multimodality therapy. This was performed in 11 patients in whom disease recurrence was suspected at a median of 9 (range, 6-16) months after treatment. PET-CT correctly diagnosed recurrent disease in eight patients and missed microscopic recurrence in one. Surveillance PET-CT was performed in 14 asymptomatic patients at a median of 11 (range, 7-13) months after treatment. It showed unsuspected recurrences in four patients. The standard uptake value max of recurrent mesothelioma was 8.9 +/- 4.0 (4-18.4). PET-CT had a sensitivity of 94%, a specificity of 100%, and the positive and negative predictive values of 100 and 88%, respectively.
18-FDG-PET-CT is useful in diagnosing disease recurrence after multimodality therapy for malignant pleural mesothelioma. We propose a prospective study to fully assess its value in this group of patients.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 03/2010; 5(3):385-8. · 4.55 Impact Factor
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Tom Treasure,
David Waller, Carol Tan,
James Entwisle,
Mary O'Brien,
Ken O'Byrne,
Gill Thomas,
Michael Snee,
James Spicer,
David Landau,
Loïc Lang-Lazdunski,
Judith Bliss,
Clare Peckitt,
Shaun Rogers,
Erica Marriage Née Denholm,
Gillian Coombes,
Mark Webster-Smith,
Julian Peto
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ABSTRACT: The effectiveness of extrapleural pneumonectomy (EPP) to extend quality-adjusted survival in malignant pleural mesothelioma within multimodality treatment should be proven in a randomized controlled trial if this radical surgery is to be regarded as the standard of care. The question was whether randomization to surgery versus no surgery would be possible.
The Mesothelioma and Radical Surgery trial was planned to randomize 50 patients to test feasibility. There was a two-stage consent process. At first consent, the patients who were possible candidates for radical surgery were registered into the trial for completion of assessment and staging. All received platinum-based chemotherapy. If still eligible, they completed a second consent to be randomized to have either EPP followed by radical hemithorax radiotherapy or to have continued best care.
Patients were recruited through 11 collaborating centers in the United Kingdom. One hundred twelve potentially eligible patients gave informed consent to enter the registration phase and undergo chemotherapy. One died, 27 progressed, five were inoperable, four were treated off trial, and 18 withdrew either during or after chemotherapy but before final review. Additionally six were deemed inoperable at review after completing chemotherapy and one more patient withdrew. The remaining 50 were randomized; 24 to EPP and 26 to continued best care.
In this study, 50/112 (45%) of patients entering the evaluation and induction phase of the trial went on to be randomized. We have shown that this randomization between surgery and no surgery is feasible. This was the primary aim of the Mesothelioma and Radical Surgery trial.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 09/2009; 4(10):1254-8. · 4.55 Impact Factor
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ABSTRACT: We set out to find a policy for the management of the pneumonectomy space which would minimise risk and be acceptable to all the surgeons. We believe this will reduce opportunities for error, be welcomed by nursing staff, and improve adherence to protocols.
We sought evidence in the scientific and educational literature. Finding no sure guidance, we audited our own experience of two policies, with the emphasis on minimising risk.
There was no evidence from randomised trials. There was no cohesive advice in the text books. Our data indicated that it was improbable that randomised controlled trial (RCT) would have the power to find the evidence. Unable to establish the best strategy, we chose what appeared to be the lowest risk management policy.
It is instructive that such a fundamental question should be unanswered. We have adopted a low risk and well established strategy--an unclamped underwater seal drain--but have no evidence base other than clinical experience. This is illustrative of much of what we do in clinical surgical practice. Avoiding major risk is often more important than proving small differences in benefit.
Heart Lung & Circulation 05/2007; 16(2):103-6. · 1.20 Impact Factor
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ABSTRACT: Dendritic cells (DC) resident in draining lymph nodes (LN) of patients with lung cancer are proposed to have a critical role in stimulating anti-tumor immunity. CpG oligodeoxynucleotides are undergoing clinical trials in patients with lung cancer and are likely to target plasmacytoid-DC. The present study, therefore, investigated the capacity of plasmacytoid-DC from human lung cancer draining LN to respond to CpG for activation of T cell responses relevant to anti-tumor immunity. The phenotype of DC was examined by flow cytometry, and cytokine production by cytometric bead array (CBA) and ELISA. Plasmacytoid-DC, purified by cell sorting, were immature but expressed the toll-like receptor, TLR9. Plasmacytoid-DC responded to the CpG oligodeoxynucleotide, CpG 2216, by production of the proinflammatory cytokines, IFN-alpha and IL-6. DC were cocultured with normal, allogeneic T cells, and cytokine production determined by CBA and immunophenotyping. CpG 2216 enhanced IFN-gamma production and induced intracellular production of IFN-gamma by CD8(+) and CD4(+), granzyme B by CD8(+), and IL-2 by CD4(+) T cells, respectively. Ligation of CD40 on plasmacytoid-DC combined with exposure to CpG 2216 also strongly enhanced IFN-gamma production. There was no significant difference between the responses of plasmacytoid-DC from patients with lung cancer and patients with benign carcinoid tumors with no pathologic LN involvement. These results indicate that plasmacytoid DC from the draining LN of patients with lung cancer effectively induce Tc1 immunity and could, therefore, represent a novel and attractive target for immunotherapeutic intervention.
American Journal of Respiratory Cell and Molecular Biology 04/2007; 36(3):360-7. · 5.13 Impact Factor
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ABSTRACT: We sought to establish the extent to which tumour uptake of [18F]-fluoro2-deoxy-glucose is associated with survival in patients with primary lung cancer. From our analysis of data concerning 498 lung cancer patients, including surgical and non-surgical cases, we conclude that there is a clear association between higher tumour uptake of glucose and worse survival.
Lung Cancer 02/2007; 55(1):75-8. · 3.43 Impact Factor
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Journal of the Royal Society of Medicine 02/2007; 100(1):10-4. · 1.41 Impact Factor
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ABSTRACT: We sought formal consensus on the appropriateness of Video-assisted Thoracoscopic Surgery (VATS) talc pleurodesis and bedside thoracostomy talc slurry by use of a well established method - the RAND/UCLA appropriateness method (RAM). We recruited an expert panel of respiratory physicians, oncologists, and surgeons under the leadership of experts in health services research. The panellists were provided with evidence from a systematic review and then were taken through two rounds of opinion gathering, the first individually, the second as a group. The purpose is not to force consensus, but to find scenarios where there is agreement on the appropriateness or inappropriateness of a treatment and scenarios where there is disagreement. In scenarios where the diagnosis was proven and expectation of life beyond six months, pleurodesis was deemed appropriate. If there was no tissue diagnosis surgical VATS was preferred. The response to a trial aspiration played a major part in the recommendation for or against pleurodesis. The attitude to breathlessness was incongruous; it is the target of palliation yet some interpreted it as performance status and thus a contraindication. Although the RAM is well developed and in widespread use, we found it worryingly unreliable and to be used with caution.
Interactive cardiovascular and thoracic surgery 07/2006; 5(3):311-6.
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ABSTRACT: The aim of this study was to review systematically the available evidence on pleurodesis for malignant effusion, focusing on the choice of the agents, route of delivery and other strategies to improve outcomes. Four electronic databases (MEDLINE, EMBASE, Web of Science and Cochrane Controlled Trials Register) were searched, reference lists checked and letters requesting details of unpublished trials and data sent to authors of previous trials. Studies of malignant pleural effusion in humans were selected with no language restrictions applied. Criteria for randomised clinical trial (RCT) eligibility were random allocation of patients and non-concurrent use of another experimental medication or device. Methodological quality evaluation of the trials was based on randomisation, blinding, allocation concealment and intention to treat analysis. A random effect model was used to combine the relative risk estimates of the treatment effects whenever pooling for an overall effect was considered appropriate. Forty-six RCTs with a total of 2053 patients with malignant pleural effusions were reviewed for effectiveness of pleurodesis. Talc tended to be associated with fewer recurrences when compared to bleomycin (RR, 0.64; 95% CI, 0.34-1.20) and, with more uncertainty, to tetracycline (RR, 0.50; 95% CI, 0.06-4.42). Tetracycline (or doxycycline) was not superior to bleomycin (RR, 0.92; 95% CI, 0.61-1.38). When compared with bedside talc slurry, thoracoscopic talc insufflation was associated with a reduction in recurrence (RR, 0.21; 95% CI, 0.05-0.93). Strategies such as rolling the patient after instillation of the sclerosing agent, protracted drainage of the effusion and use of larger chest tubes were not found to have any substantial advantages. Talc appears to be effective and should be the agent of choice for pleurodesis. Thoracoscopic talc insufflation is associated with fewer recurrences of effusions compared with bedside talc slurry, but this is based on two small studies. Where thoracoscopy is unavailable bedside talc pleurodesis has a high success rate and is the next best option.
European Journal of Cardio-Thoracic Surgery 06/2006; 29(5):829-38. · 2.55 Impact Factor
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Journal of the Royal Society of Medicine 05/2006; 99(4):164-5. · 1.41 Impact Factor
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Journal of the Royal Society of Medicine 03/2006; 99(2):77-80. · 1.41 Impact Factor
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ABSTRACT: The increasing incidence of malignant pleural mesothelioma has demanded the attention of thoracic surgeons worldwide. Can radical surgery cure mesothelioma or add usefully to the length and quality of life for its victims? The MARS (mesothelioma and radical surgery) trial is open and recruiting in Britain. If the trial proves feasible we will seek to make an international study.
Interactive cardiovascular and thoracic surgery 03/2006; 5(1):58-9.
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Journal of the Royal Society of Medicine 11/2005; 98(10):455-8. · 1.41 Impact Factor
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Journal of Thoracic and Cardiovascular Surgery 06/2005; 129(5):1202; author reply 1202-3. · 3.41 Impact Factor
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ABSTRACT: Asbestos exposure in industry and construction sites in the 1960s and 1970s has left a legacy of mesothelioma, a diffuse pleural cancer, with a lag time of 40 to 50 years and due to peak around 2015 to 2020. Some surgeons believe that by radical surgery they can prolong life and relieve symptoms, but the evidence comes from very carefully selected series. How do surgeons respond to demand for evidence of benefit? In this article we explore how evidence for major surgical operations has been gained and how mesothelioma fits into this history.
World Journal of Surgery 09/2003; 27(8):891-4. · 2.36 Impact Factor
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ABSTRACT: A 5-month-old girl presented with upper airway obstruction and was found to have a mediastinal mass compressing the trachea. She successfully underwent resection of this mass, later confirmed to be a juvenile haemangioma. This case highlights mediastinal haemangiomas in the paediatric population as a diagnostic and therapeutic challenge, and the importance of a multidisciplinary approach in the management of such patients.
European Journal of Cardio-Thoracic Surgery 07/2003; 23(6):1065-7. · 2.55 Impact Factor
