Natalie Zahan-Evans

Predicting survival in malignant pleural effusion: development and validation of the LENT prognostic score

Background Malignant pleural effusion (MPE) causes debilitating breathlessness and predicting survival is challenging. This study aimed to obtain contemporary data on survival by underlying tumour type in patients with MPE, identify prognostic indicators of overall survival and develop and validate a prognostic scoring system. Methods Three large international cohorts of patients with MPE were used to calculate survival by cell type (univariable Cox model). The prognostic value of 14 predefined variables was evaluated in the most complete data set (multivariable Cox model). A clinical prognostic scoring system was then developed and validated. Results Based on the results of the international data and the multivariable survival analysis, the LENT prognostic score (pleural fluid lactate dehydrogenase, Eastern Cooperative Oncology Group (ECOG) performance score (PS), neutrophil-to-lymphocyte ratio and tumour type) was developed and subsequently validated using an independent data set. Risk stratifying patients into low-risk, moderate-risk and high-risk groups gave median (IQR) survivals of 319 days (228–549; n=43), 130 days (47–467; n=129) and 44 days (22–77; n=31), respectively. Only 65% (20/31) of patients with a high-risk LENT score survived 1 month from diagnosis and just 3% (1/31) survived 6 months. Analysis of the area under the receiver operating curve revealed the LENT score to be superior at predicting survival compared with ECOG PS at 1 month (0.77 vs 0.66, p<0.01), 3 months (0.84 vs 0.75, p<0.01) and 6 months (0.85 vs 0.76, p<0.01). Conclusions The LENT scoring system is the first validated prognostic score in MPE, which predicts survival with significantly better accuracy than ECOG PS alone. This may aid clinical decision making in this diverse patient population.

Prophylactic radiotherapy for the prevention of procedure-tract metastases after surgical and large-bore pleural procedures in malignant pleural mesothelioma (SMART): a multicentre, open-label, phase 3, randomised controlled trial

Summary Background The use of prophylactic radiotherapy to prevent procedure-tract metastases (PTMs) in malignant pleural mesothelioma remains controversial, and clinical practice varies worldwide. We aimed to compare prophylactic radiotherapy with deferred radiotherapy (given only when a PTM developed) in a suitably powered trial. Methods We did a multicentre, open-label, phase 3, randomised controlled trial in 22 UK hospitals of patients with histocytologically proven mesothelioma who had undergone large-bore pleural interventions in the 35 days prior to recruitment. Eligible patients were randomised (1:1), using a computer-generated sequence, to receive immediate radiotherapy (21 Gy in three fractions within 42 days of the pleural intervention) or deferred radiotherapy (same dose given within 35 days of PTM diagnosis). Randomisation was minimised by histological subtype, surgical versus non-surgical procedure, and pleural procedure (indwelling pleural catheter vs other). The primary outcome was the incidence of PTM within 7 cm of the site of pleural intervention within 12 months from randomisation, assessed in the intention-to-treat population. This trial is registered with ISRCTN, number ISRCTN72767336. Findings Between Dec 23, 2011, and Aug 4, 2014, we randomised 203 patients to receive immediate radiotherapy (n=102) or deferred radiotherapy (n=101). The patients were well matched at baseline. No significant difference was seen in PTM incidence in the immediate and deferred radiotherapy groups (nine [9%] vs 16 [16%]; odds ratio 0·51 [95% CI 0·19–1·32]; p=0·14). The only serious adverse event related to a PTM or radiotherapy was development of a painful PTM within the radiotherapy field that required hospital admission for symptom control in one patient who received immediate radiotherapy. Common adverse events of immediate radiotherapy were skin toxicity (grade 1 in 50 [54%] and grade 2 in four [4%] of 92 patients vs grade 1 in three [60%] and grade 2 in two [40%] of five patients in the deferred radiotherapy group who received radiotherapy for a PTM) and tiredness or lethargy (36 [39%] in the immediate radiotherapy group vs two [40%] in the deferred radiotherapy group) within 3 months of receiving radiotherapy. Interpretation Routine use of prophylactic radiotherapy in all patients with mesothelioma after large-bore thoracic interventions is not justified. Funding Research for Patient Benefit Programme from the UK National Institute for Health Research.

Indwelling pleural catheters for non-malignant effusions: a multicentre review of practice

Indwelling pleural catheters (IPCs) are commonly used in the management of malignant pleural effusion (MPE). There is little data on their use in non-malignant conditions. All IPC insertions for non-malignant cases from five large UK centres were found using prospectively maintained databases. Data were collected on 57 IPC insertions. The commonest indications were hepatic hydrothorax (33%) and inflammatory pleuritis (26%). The mean weekly fluid output was 2.8 L (SD 2.52). 48/57 (84%) patients had no complications. Suspected pleural infection was documented in 2 (3.5%) cases. 33% (19/57) of patients underwent ‘spontaneous’ pleurodesis at a median time of 71 days. Patients with hepatic disease achieved pleurodesis significantly less often than those with non-hepatic disease (p=0.03). These data support the use of IPCs in select cases of non-malignant disease when maximal medical therapy has failed.

Pleural irrigation trial (PIT): a randomised controlled trial of pleural irrigation with normal saline versus standard care in patients with pleural infection

Pleural infection is increasing in incidence. Despite optimal medical management, up to 30% of patients will die or require surgery. Case reports suggest that irrigation of the pleural space with saline may be beneficial. A randomised controlled pilot study in which saline pleural irrigation (three times per day for 3 days) plus best-practice management was compared with best-practice management alone was performed in patients with pleural infection requiring chest-tube drainage. The primary outcome was percentage change in computed tomography pleural fluid volume from day 0 to day 3. Secondary outcomes included surgical referral rate, hospital stay and adverse events. 35 patients were randomised. Patients receiving saline irrigation had a significantly greater reduction in pleural collection volume on computed tomography compared to those receiving standard care (median (interquartile range) 32.3% (19.6–43.7%) reduction versus 15.3% (−5.5–28%) reduction) (p<0.04). Significantly fewer patients in the irrigation group were referred for surgery (OR 7.1, 95% CI 1.23–41.0; p=0.03). There was no difference in length of hospital stay, fall in C-reactive protein, white cell count or procalcitonin or adverse events between the treatment groups, and no serious complications were documented. Saline irrigation improves pleural fluid drainage and reduces referrals for surgery in pleural infection. A large multicentre randomised controlled trial is now warranted to evaluate its effects further. Does pleural irrigation improve pleural fluid drainage and resolution of sepsis in pleural infection? http://ow.ly/KPHeM

Outpatient Talc Administration by Indwelling Pleural Catheter for Malignant Effusion

BACKGROUND Malignant pleural effusion affects more than 750,000 persons each year across Europe and the United States. Pleurodesis with the administration of talc in hospitalized patients is the most common treatment, but indwelling pleural catheters placed for drainage offer an ambulatory alternative. We examined whether talc administered through an indwelling pleural catheter was more effective at inducing pleurodesis than the use of an indwelling pleural catheter alone. METHODS Over a period of 4 years, we recruited patients with malignant pleural effusion at 18 centers in the United Kingdom. After the insertion of an indwelling pleural catheter, patients underwent drainage regularly on an outpatient basis. If there was no evidence of substantial lung entrapment (nonexpandable lung, in which lung expansion and pleural apposition are not possible because of visceral fibrosis or bronchial obstruction) at 10 days, patients were randomly assigned to receive either 4 g of talc slurry or placebo through the indwelling pleural catheter on an outpatient basis. Talc or placebo was administered on a single‐blind basis. Follow‐up lasted for 70 days. The primary outcome was successful pleurodesis at day 35 after randomization. RESULTS The target of 154 patients undergoing randomization was reached after 584 patients were approached. At day 35, a total of 30 of 69 patients (43%) in the talc group had successful pleurodesis, as compared with 16 of 70 (23%) in the placebo group (hazard ratio, 2.20; 95% confidence interval, 1.23 to 3.92; P=0.008). No significant between‐group differences in effusion size and complexity, number of inpatient days, mortality, or number of adverse events were identified. No significant excess of blockages of the indwelling pleural catheter was noted in the talc group. CONCLUSIONS Among patients without substantial lung entrapment, the outpatient administration of talc through an indwelling pleural catheter for the treatment of malignant pleural effusion resulted in a significantly higher chance of pleurodesis at 35 days than an indwelling catheter alone, with no deleterious effects. (Funded by Becton Dickinson; EudraCT number, 2012–000599–40.)

Pleural fluid adenosine deaminase (pfada) in the diagnosis of tuberculous effusions in a low incidence population

Introduction Previous studies have assessed the diagnostic ability of pleural fluid adenosine deaminase (pfADA) in detecting tuberculous pleural effusions, with good specificity and sensitivity reported. However, in North Western Europe pfADA is not routinely used in the investigation of a patient with an undiagnosed pleural effusion, mainly due to a lack of evidence as to its utility in populations with low mycobacterium tuberculosis (mTB) incidence. Methods Patients presenting with an undiagnosed pleural effusion to a tertiary pleural centre in South-West England over a 3 year period, were prospectively recruited to a pleural biomarker study. Pleural fluid from consecutive patients with robust 12-month follow up data and confirmed diagnosis were sent for pfADA analysis. Results Of 338 patients enrolled, 7 had confirmed tuberculous pleural effusion (2%). All mTB effusions were lymphocyte predominant with a median pfADA of 72.0 IU/L (range- 26.7 to 91.5) compared to a population median of 12.0 IU/L (range- 0.3 to 568.4). The optimal pfADA cut off was 35 IU/L, which had a negative predictive value (NPV) of 99.7% (95% CI; 98.2-99.9%) for the exclusion of mTB, and sensitivity of 85.7% (95% CI; 42.2-97.6%) with an area under the curve of 0.88 (95% CI; 0.732–1.000). Discussion This is the first study examining the diagnostic utility of pfADA in a low mTB incidence area. The chance of an effusion with a pfADA under 35 IU/L being of tuberculous aetiology was negligible. A pfADA of over 35 IU/L in lymphocyte-predominant pleural fluid gives a strong suspicion of mTB.

A Randomised Controlled Trial of Intravenous Zoledronic Acid in Malignant Pleural Disease: A Proof of Principle Pilot Study

Introduction Animal studies have shown Zoledronic Acid (ZA) may diminish pleural fluid accumulation and tumour bulk in malignant pleural disease (MPD). We performed a pilot study to evaluate its effects in humans. Methods We undertook a single centre, double-blind, placebo-controlled trial in adults with MPD. Patients were randomised (1:1) to receive 2 doses of intravenous ZA or placebo, 3 weeks apart and were followed-up for 6 weeks. The co-primary outcomes were change in Visual Analogue Scale (VAS) score measured breathlessness during trial follow-up and change in the initial area under the curve (iAUC) on thoracic Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) from randomisation to week 5. Multiple secondary endpoints were also evaluated. Results Between January 2010 and May 2013, 30 patients were enrolled, 24 randomised and 4 withdrew after randomisation (1 withdrew consent; 3 had a clinical decline). At baseline, the ZA group were more breathless, had more advanced disease on radiology and worse quality of life than the placebo group. There was no significant difference between the groups with regards change in breathlessness (Adjusted mean difference (AMD) 4.16 (95%CI −4.7 to 13.0)) or change in DCE-MRI iAUC (AMD −15.4 (95%CI −58.1 to 27.3). Two of nine (22%) in the ZA arm had a >10% improvement by modified RECIST (vs 0/11 who received placebo). There was no significant difference in quality of life measured by the QLQ-C30 score (global QOL: AMD -4.1 (-13.0 to 4.9)), side effects or serious adverse event rates. Conclusions This is the first human study to evaluate ZA in MPD. The study is limited by small numbers and imbalanced baseline characteristics. Although no convincing treatment effect was identified, potential benefits for specific subgroups of patients cannot be excluded. This study provides important information regarding the feasibility of future trials to evaluate the effects of ZA further. Trial Registration UK Clinical Research Network ID 8877 ISRCTN17030426 www.isrctn.com

P209 The clinical utility of pleural lymphocyte subset analysis in undiagnosed effusions

Introduction Blood and tissue lymphocyte subsets (LS) analysis are routinely used in the diagnosis of a number of haematological conditions. Samples cost £25 to process and are technically labour intensive. The 2010 BTS pleural guidelines suggest LS may be useful in cases of suspected lymphoma, but there is no evidence supporting their utility or position in pleural diagnostic algorithms. Methods Using a prospectively-maintained database of all undiagnosed pleural effusions, we analysed patients presenting to our service from 2009–2011. Fluid was initially sent for cytology and cell differential. Patients with ≥ 50% fluid lymphocytes at first sampling, with no definite cytological evidence of carcinoma, and who underwent a further pleural procedure, had a second sample sent for LS analysis. The cause of the original effusion was agreed by two independent consultants after a minimum 12 month follow-up period. Results 395 patients with undiagnosed effusions were seen, of which 124(31%) were found to be lymphocytic on initial examination. 35(28.2%) patients were excluded due to confirmed (non-haematological) malignancy (11 initial cytology, 24 biopsy). A further 46(37.1%) patients were excluded with confirmed benign diagnoses including inflammatory pleuritis, heart failure and pleural infection. 39/43 (90.7%) patients therefore had samples sent for LS analysis. 7/43 (16.3%) patients’ effusions were diagnosed at 12 months as primarily due to lymphoma, with 5 having a previous diagnosis of such. Their characteristics are described in the table below. LS analysis was diagnostic in 4 and negative in 35 cases. There were no false positive results. Therefore, based on these data, for determining whether there is haematological malignancy in lymphocytic pleural fluid, LS analysis has a sensitivity of 57.1%, a specificity of 100%, and a positive and negative predictive value of 100% and 91.4% respectively. Conclusions LS analysis appears useful in a selected subgroup of patients presenting with undiagnosed effusions. It should only be considered in those patients with a lymphocytic effusion which shows negative initial cytology and/or no firm diagnosis established on pleural biopsy, or those with a past medical history of a lymphoma. A negative LS result does not exclude the possibility of a haematological cause for the effusion. Abstract P209 Table 1. Investigations and characteristics of patients with confirmed lymphoma who underwent pleural fluid lymphocyte subsets analysis. Patient Disease Comorbidities History of lymphoma LS positive Tissue obtained Tissue diagnostic? 1 DLBCL Nil No No Marrow Yes 2 DLBCL AF Yes Yes Marrow No 3 DLBCL CCF, AF Yes No Node Yes 4 Low grade NHL Nil Yes Yes Too frail 5 Low grade NHL Nil Yes No Too frail 6 CLL Nil Yes Yes No 7 CLL T2DM, AF No Yes Thoracoscopy Yes DLBCL=Diffuse large B-cell Lymphoma, NHL=Non-Hodgkin’s Lymphoma, CLL=Chronic Lymphocytic Leukaemia

S25 Eosinophilic pleural effusions – a large prospective study on aetiology and prognosis

Introduction and Objectives Eosinophilic pleural effusions (EPE) are a relatively uncommon finding in the investigation of undifferentiated pleural effusions. Traditionally defined as a cell count ≥10% eosinophils, it was initially felt to be a marker of benign disease, however, subsequent studies found malignancy to be the commonest aetiology,1 with other causes, including infection, blood/air and drug reactions less frequent. Our aim is to use prospective data to examine the relative incidence and aetiology of EPE, and its prognostic significance. Methods We recruited 803 consecutive patients presenting to a pleural service, between 03/2008 and 03/2015, with undiagnosed pleural effusions. Pleural biochemistry, cytology, thoracic USS, chest radiograph and CT scans were performed. Biopsies and thoracoscopy were performed as clinically indicated. Patients were followed-up for minimum duration of 12 months with final diagnosis decided by independent review by 2 respiratory consultants. Survival data was calculated from study entry to death and censored on 07/2017. Results Of the 803 patients, 398/803 (49.6%) had a malignant pleural effusion(MPE). 57 (7.1%) had eosinophil count (EC) ≥10%. With this threshold, MPE was the commonest cause, at 24/57 (42%), followed by infection 9 (16%) and inflammatory pleuritis (IP) 5 (9%). With higher thresholds of EC, the relative frequency of malignancy decreased. At ≥30% EC, malignancy accounted for 4/20 cases, infection 4/20, drug/toxin 3/20, unknown 3/20, benign asbestos pleural effusion 2/20, pulmonary embolism 2/20, IP 1/20 and heart failure 1/20. Mortality rates were lower in EPE relative to non-EPE, with 6 months and 1 year mortality rates for EPE 19%–33% respectively, with non-EPE 36%–50%. The higher the EC, the lower mortality, with hazard ratios compared to non-EPE at 0.6, 0.5, 0.3, 0.2, 0.2 for ≥10%,≥20%,≥30%,≥40% and ≥50% EC respectively (p<0.01). Conclusion Higher eosinophil counts are associated with decreased mortality and lower rates of malignant vs benign effusions. The threshold ≥10% is not helpful in differentiating MPE from benign disease. We suggest a higher threshold of ≥30% would hold greater clinical significance and therefore be a more useful definition for clinicians. Reference Rubins JB, Rubins HB. Aetiology and prognostic significance of eosinophilic pleural effusions: A prospective study. Chest 1996;110(5):1271–4. Abstract S25 Figure 1 Kaplan-meier survival curves for Eosinophilic vs Non-Eosinophilic effusions.

A Prospective Study to Evaluate a Diagnostic Algorithm for the Use of Fluid Lymphocyte Subset Analysis in Undiagnosed Unilateral Pleural Effusions

Background: Haematological malignancy is an important cause of pleural effusion. Pleural effusions secondary to haematological malignancy are usually lymphocyte predominant. However, several other conditions such as carcinoma, tuberculosis, and chronic heart failure also cause lymphocytic effusions. Lymphocyte subset (LS) analysis may be a useful test to identify haematological malignancy in patients with lymphocytic effusions. However, research into their utility in pleural effusion diagnostic algorithms has not yet been published. Objectives: We aimed to determine the clinical utility of pleural fluid LS analysis and whether it can be applied to a diagnostic algorithm to identify effusions secondary to haematological malignancy. The secondary aim was to evaluate the diagnostic value of pleural fluid differential cell count. Methods: Consecutive consenting patients presenting to our pleural service between 2008 and 2013 underwent thoracentesis and differential cell count analysis. We proposed an algorithm which selected patients with lymphocytic effusions (>50%) to have further fluid sent for LS analysis. Two independent consultants agreed on the cause of the original effusion after a 12-month follow-up period. Results: A total of 60 patients had samples sent for LS analysis. LS analysis had an 80% sensitivity (8/10) and a 100% specificity for the diagnosis of haematological malignancy. The positive and negative predictive values were 100 and 96.1%, respectively. Overall 344 differential cell counts were analysed; 16% of pleural effusions with a malignant aetiology were neutrophilic or eosinophilic at presentation. A higher neutrophil and eosinophil count was associated with benign diagnoses, whereas a higher lymphocyte count was associated with malignant diagnoses. Conclusions: LS analysis may identify haematological malignancy in a specific cohort of patients with undiagnosed pleural effusions. A pleural fluid differential cell count provides useful additional information to streamline patient pathway decisions.