Use of lipoteichoic acid-T for pleurodesis in malignant pleural effusion: a phase I toxicity and dose-escalation study

• Published in: The lancet oncology 2008-10, Vol.9 (10), p.946-952
• Main Authors: Rahman, Najib M, MRCP, Davies, Helen E, MRCP, Salzberg, Marc, Truog, Peter, MD, Midgely, Rachel, FRCP, Kerr, David, Prof, Clelland, Colin, FRCPath, Hedley, Emma L, Lee, YC Gary, PhD, Davies, Robert JO, Prof
• Format: Article
• Language: English
• Subjects: Adult; Cytokines - analysis; Dose-Response Relationship, Drug; Drainage; Female; Hematology, Oncology and Palliative Medicine; Humans; Leukocyte Count; Lipopolysaccharides - administration & dosage; Lipopolysaccharides - adverse effects; Male; Middle Aged; Pleural Effusion, Malignant - pathology; Pleural Effusion, Malignant - physiopathology; Pleural Effusion, Malignant - therapy; Pleurodesis - methods; Teichoic Acids - administration & dosage; Teichoic Acids - adverse effects
• ISSN: 1470-2045; 1474-5488
• DOI: 10.1016/S1470-2045(08)70205-5

Summary Background Bacterial infection of the pleural space often causes adherence of the pleural membranes by fibrous tissue, probably mediated by inflammation initiated by bacterial cell-wall motifs, including lipoteichoic acid-T (LTA-T). We postulated that therapeutically administered LTA-T might produce a similar effect, achieving control of malignant pleural effusion (pleurodesis). Methods Patients with histocytologically proven symptomatic malignant pleural effusions were included in this phase I toxicity and dose-escalation study, An indwelling pleural catheter was placed in the pleural effusion to drain the fluid fully. A control dose of intrapleural saline was administered after complete drainage (day 1) and pleural-fluid production was recorded for 7 days. On day 7 a single dose of intrapleural LTA-T (increasing in each patient) was administered and pleural-fluid production was monitored for a further 7 days. Long-term fluid control was recorded. This study is registered as an International Standard Randomised Controlled Trial, ISRCTN44367564. Findings Between November, 2004, and November, 2005, 14 patients were enrolled on the trial at the Oxford Centre for Respiratory Medicine (Oxford, UK). 13 of 14 patients received escalated doses of LTA-T. A dose-limiting toxic effect (ie, systemic inflammation) occurred at 3000 μg, and a therapeutic dose of 750–1500 μg was established. Toxic effects were mild and had no consistent pattern at the therapeutic dose. Pleural-fluid production decreased significantly after a dose of at least 750 μg LTA-T, compared with saline control (mean fluid production after saline control 1244 mL [SD 933], mean fluid production after LTA-T 394 mL [SD 375], mean difference −850 mL [SD 699], p=0·028), and six of seven (86%) patients achieved pleural-fluid control at 1 month with no further intervention. Interpretation The toxic effects of intrapleural LTA-T seem to be mild and favourable when compared with the toxicity profiles of standard pleurodesis agents. There is early evidence of LTA-T-induced pleurodesis efficacy, suggesting that this might be a viable therapeutic strategy for the control of malignant pleural effusion. Funding Lunamed, Chur, Switzerland.