Anna J Morley

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.

A prospective trial evaluating the role of mesothelin in undiagnosed pleural effusions

Mesothelin has been proposed as a useful tool in the diagnosis of malignant pleural mesothelioma (MPM). We aimed to examine its diagnostic utility and the impact of renal impairment on results. We prospectively recruited 230 patients with new undiagnosed pleural effusions, testing serum (n=216) and pleural fluid (n=206) mesothelin (by ELISA) during the initial consultation. 28 (12%) out of 230 patients had MPM. Serum mesothelin gave sensitivity 59.3%, specificity 64.7%, negative predictive value (NPV) 91.2%, positive predictive value (PPV) 20.5%, and pleural fluid sensitivity 72.0%, specificity 87.5%, NPV 95.5%, PPV 46.2% for distinguishing effusions due to MPM. In a matched comparison, diagnostic characteristics of pleural fluid mesothelin were superior to serum (p=0.0001). Serum mesothelin levels in patients without MPM were higher in patients with renal impairment (p=0.007) while pleural fluid levels were unaffected. 19 (54%) out of 35 patients with a benign pleural effusion and an estimated glomerular filtration rate ≤59 mL·min−1 had a false-positive serum mesothelin result. The diagnostic accuracy of pleural fluid mesothelin is superior to that of serum and is unaffected by renal function. In patients with a low pre-test probability of mesothelioma, a negative mesothelin test could be reassuring, because of its high NPV. Routine use of mesothelin testing in undiagnosed pleural effusions at presentation appears to be unhelpful.

The South West Area Mesothelioma and Pemetrexed trial: a multicentre prospective observational study evaluating novel markers of chemotherapy response and prognostication

Background:Robust markers that predict prognosis and detect early treatment response in malignant pleural mesothelioma (MPM) would enhance patient care.Methods:Consecutive patients with MPM who were considered fit for first-line chemotherapy were prospectively recruited. Patients of similar performance status opting for best supportive care were included as a comparator group. Baseline and interval CT, PET-CT and serum markers (mesothelin, fibulin-3 and neutrophil–lymphocyte ratio (NLR)) were obtained, and patients followed up for a minimum 12 months.Findings:Seventy-three patients were recruited (58 chemotherapy/15 comparator arm). Baseline TGV (total glycolytic volume on PET-CT) was an independent predictor of worse overall survival (OS) (P=0.001). Change in interval TGV(baseline/after two cycles of chemotherapy) did not predict OS or chemotherapy response on CT. Baseline NLR<4 was an independent predictor of better OS (median survival 453 (IQR 272–576) days vs NLR⩾4, 257 (IQR 147–490), P=0.002). Although baseline serum mesothelin did not predict OS, a falling level at 8 weeks significantly predicted longer time to progression (TTP) (P<0.001).Interpretation:Neutrophil–lymphocyte ratio and baseline TGV predict prognosis in malignant pleural mesothelioma (MPM), but PET-CT is unhelpful in monitoring chemotherapy response. Serum mesothelin is a useful early treatment response marker when measured serially during chemotherapy and may have a role in evaluating patients’ treatment response.

The efficacy of indwelling pleural catheter placement versus placement plus talc sclerosant in patients with malignant pleural effusions managed exclusively as outpatients (IPC-PLUS): study protocol for a randomised controlled trial.

BackgroundMalignant pleural effusions (MPEs) remain a common problem, with 40,000 new cases in the United Kingdom each year and up to 250,000 in the United States. Traditional management of MPE usually involves an inpatient stay with placement of a chest drain, followed by the instillation of a pleural sclerosing agent such as talc, which aims to minimise further fluid build-up. Despite a good success rate in studies, this approach can be expensive, time-consuming and inconvenient for patients. More recently, an alternative method has become available in the form of indwelling pleural catheters (IPCs), which can be inserted and managed in an outpatient setting. It is currently unknown whether combining talc pleurodesis with IPCs will provide improved pleural symphysis rates over those of IPCs alone.Methods/DesignIPC-PLUS is a patient-blind, multicentre randomised controlled trial (RCT) comparing the combination of talc with an IPC to the use of an IPC alone for inducing pleurodesis in MPEs. The primary outcome is successful pleurodesis at five weeks post-randomisation. This study will recruit 154 patients, with an interim analysis for efficacy after 100 patients, and aims to help to define the future gold standard for outpatient management of patients with symptomatic MPEs.DiscussionIPC-PLUS is the first RCT to examine the practicality and utility of talc administered via an IPC. The study remains in active recruitment and has the potential to significantly alter how patients requiring pleurodesis for MPE are approached in the future.Trial registrationThis trial was registered with Current Controlled Trials (identifier: ISRCTN73255764) on 23 August 2012.

Testing mapping algorithms of the cancer-specific EORTC QLQ-C30 onto EQ-5D in malignant mesothelioma

BackgroundIn order to estimate utilities for cancer studies where the EQ-5D was not used, the EORTC QLQ-C30 can be used to estimate EQ-5D using existing mapping algorithms. Several mapping algorithms exist for this transformation, however, algorithms tend to lose accuracy in patients in poor health states. The aim of this study was to test all existing mapping algorithms of QLQ-C30 onto EQ-5D, in a dataset of patients with malignant pleural mesothelioma, an invariably fatal malignancy where no previous mapping estimation has been published.MethodsHealth related quality of life (HRQoL) data where both the EQ-5D and QLQ-C30 were used simultaneously was obtained from the UK-based prospective observational SWAMP (South West Area Mesothelioma and Pemetrexed) trial. In the original trial 73 patients with pleural mesothelioma were offered palliative chemotherapy and their HRQoL was assessed across five time points. This data was used to test the nine available mapping algorithms found in the literature, comparing predicted against observed EQ-5D values. The ability of algorithms to predict the mean, minimise error and detect clinically significant differences was assessed.ResultsThe dataset had a total of 250 observations across 5 timepoints. The linear regression mapping algorithms tested generally performed poorly, over-estimating the predicted compared to observed EQ-5D values, especially when observed EQ-5D was below 0.5. The best performing algorithm used a response mapping method and predicted the mean EQ-5D with accuracy with an average root mean squared error of 0.17 (Standard Deviation; 0.22). This algorithm reliably discriminated between clinically distinct subgroups seen in the primary dataset.ConclusionsThis study tested mapping algorithms in a population with poor health states, where they have been previously shown to perform poorly. Further research into EQ-5D estimation should be directed at response mapping methods given its superior performance in this study.

Survival in Patients With Malignant Pleural Effusions Who Developed Pleural Infection: A Retrospective Case Review From Six UK Centers.

OBJECTIVE Malignant pleural effusion (MPE) incidence is increasing, and prognosis remains poor. Indwelling pleural catheters (IPCs) relieve symptoms but increase the risk of pleural infection. We reviewed cases of pleural infection in patients with IPCs for MPE from six UK centers between January 1, 2005, and January 31, 2014. METHODS Survival in patients with pleural infection was compared with 788 patients with MPE (known as the LENT [pleural fluid lactate dehydrogenase, Eastern Cooperative Oncology Group performance status, serum neutrophil to lymphocyte ratio, and tumor type] cohort) and with national statistics. RESULTS Of 672 IPCs inserted, 25 (3.7%) became infected. Most patients (20 of 25) had mesothelioma or lung cancer. Median survival in the pleural infection cohort appeared longer than in the LENT cohort, although this result did not achieve significance (386 days vs 132 days; hazard ratio, 0.67; P = .07). Median survival with mesothelioma and pleural infection was twice as long as national estimates for mesothelioma survival (753 days vs < 365 days) and double the median survival of patients with mesothelioma in the LENT cohort (339 days; 95% CI, nonoverlapping). Survival with lung and breast cancer did not differ significantly between the groups. Sixty-one percent of patients experienced early infection. There was no survival difference between patients with early and late infection (P = .6). CONCLUSIONS This small series of patients with IPCs for MPE suggests pleural infection may be associated with longer survival, particularly in patients with mesothelioma. Results did not achieve significance, and a larger study is needed to explore this relationship further and investigate whether the local immune response, triggered by infection, is able to modulate mesothelioma progression.

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

The Role of CT Pulmonary Angiography in the Investigation of Unilateral Pleural Effusions

Background: Pulmonary embolism (PE) is frequently cited as a common primary cause of unilateral pleural effusion, but in clinical practice appears to be uncommon. Objectives: In order to evaluate this observation, CT pulmonary angiography (CTPA) was performed in consecutive patients presenting to a single centre with a new uninvestigated unilateral pleural effusion and no clear cause and was supplemented by delayed-phase thoracic CT, optimized for visualization of the pleura. Methods: All patients underwent standard clinical assessment and pleural investigations in line with recent national guidelines and were followed up for a minimum of 1 year or until histological/microbiological diagnosis. Results: One hundred and fifty patients were recruited, and of these, 141 had a CTPA. PEs were detected in 9/141 (6.4%) patients, and of these, 8/9 were subsequently diagnosed with pleural malignancy. In only 1 case was PE clinically suspected and in no case was PE the primary cause of effusion; 9.8% (8/82) of patients who were ultimately diagnosed with pleural malignancy had PE at presentation. Conclusions: This study indicates that PE is a frequent concomitant finding in patients with malignant effusions but uncommon as a primary cause of unilateral effusion. In addition, it highlights the known difficulty of clinical diagnosis of PE in the context of malignancy. In view of this, we recommend that CTPA combined with pleural-phase thoracic CT should be considered at presentation when investigating patients with suspected malignant pleural effusion.

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.)