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A randomised controlled trial of intravenous zoledronic acid in malignant pleural disease: a proof of principle pilot study.

ABSTRACT: 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.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.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.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.UK Clinical Research Network ID 8877 ISRCTN17030426 www.isrctn.com.

SUBMITTER: Clive AO

PROVIDER: S-EPMC4364455 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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A randomised controlled trial of intravenous zoledronic acid in malignant pleural disease: a proof of principle pilot study.

Clive Amelia O AO Hooper Clare E CE Edey Anthony J AJ Morley Anna J AJ Zahan-Evans Natalie N Hall David D Lyburn Iain I White Paul P Braybrooke Jeremy P JP Sequeiros Iara I Lyen Stephen M SM Milton Tim T Kahan Brennan C BC Maskell Nick A NA

PloS one 20150317 3

<h4>Introduction</h4>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.<h4>Methods</h4>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 ...[more]

PMID: 25781025

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Project description:PURPOSE:Malignant pleural mesothelioma (MPM) is a rare malignancy with a dismal median survival of <12 months with current therapy. Single and combination chemotherapy regimens have shown only modest clinical benefit. In preclinical studies, nitrogen-containing bisphosphonates (zoledronic acid) inhibit growth of mesothelioma cells by different mechanisms: inhibition of mevalonate pathway, inhibition of angiogenesis, activation of apoptosis through caspase activation, and alteration in activity of matrix metalloproteinases, thereby affecting invasiveness of cancer cells. PATIENTS AND METHODS:We investigated the role of zoledronic acid in a pilot, single-arm trial of MPM patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2 who had progressed on prior treatments or had not received systemic therapy due to poor PS. Primary end point was composite response rate by modified response evaluation criteria in solid tumors and/or metabolic response by 2-deoxy-2-[fluorine-18]fluoro-d-glucose (18F-FDG) positron emission tomography criteria. Secondary end points were progression-free survival (PFS) and overall survival (OS). Exploratory end points include the effect of zoledronic acid therapy on vascular endothelial growth factor (VEGF), basic fibroblast growth factor, interleukin 8, transforming growth factor beta, mesothelin, and osteopontin levels. RESULTS:Eight male patients (median age of 62 years) with the following clinical characteristics were treated; ECOG PS was 0-2, 75% with epithelioid type, and 62% had prior chemotherapy Overall composite response rate was 12.5% and the clinical benefit rate (response + stable disease) was 37.5%. Median PFS was 2 months (0.5-21 months) and median OS was 7 months (0.8-28 months). No treatment-related toxicities were observed. Lower VEGF levels were predictive of favorable response and mesothelin levels correlated with disease course. CONCLUSION:Zoledronic acid shows modest clinical activity without significant toxicity in patients with advanced MPM.

Project description:INTRODUCTION:Dehydroepiandrosterone (DHEA) has been proposed to improve pregnancy rates in women with diminished ovarian reserve undergoing in vitro fertilisation (IVF) treatment. However, evidence regarding its efficacy is supported by a limited number of randomised controlled trials (RCTs). This double-blinded RCT aims to measure the effect of DHEA supplementation prior to and during controlled ovarian hyperstimulation on ovarian response prior to IVF treatment in women predicted to have poor ovarian reserve. METHODS AND ANALYSIS:Sixty women with ovarian antral follicle count ?10 and serum anti-Mullerian hormone ?5 pmol/L undergoing IVF/intracytoplasmic sperm injection (ICSI) treatment at the Nurture fertility clinic, Nottingham will be recruited. They will be randomised to either receive DHEA capsule 75?mg/day or placebo for at least 12?weeks before egg collection. All participants will undergo standard long down regulation protocol using human menopausal gonadotropin 300?IU/day. Serum samples and follicular fluids at the time of egg collection will be collected for hormonal immunoassays. For ICSI participants, cumulus cells stripped from oocyte will be collected for cumulus gene expression analyses regarding oocyte competence. Microdrops of oocyte culture media before the time of ICSI will be assessed for glucose, pyruvate and lactate utilisation. Embryo transfer will be performed on day 2, 3 or 5 based on the number and quality of the embryos available. Pregnancy will be defined as urine pregnancy test positive (biochemical pregnancy) and 6-8?weeks ultrasound scan with fetal heart beat (clinical pregnancy) and live birth. It is planned to perform the molecular and nutritional fingerprint analyses in batches after finishing the clinical phase of the study. ETHICS AND DISSEMINATION:The approval of the study was granted by the NHS Research Ethics Committee (Ref number NRES 12/EM/0002), the Medicines and Healthcare products Regulatory Agency (MHRA), and the Nottingham University Hospitals Trust Research and Development department. All participants shall provide written informed consent before being randomised into allocated treatment groups. TRIAL REGISTRATION NUMBER:Protocol V.2.0; EudraCT number: 2011-002425-21; http://www.clinicaltrials.gov; NCT01572025; CTA reference: 03057/0053/001-0002.

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A randomised controlled trial of intravenous zoledronic acid in malignant pleural disease: a proof of principle pilot study.

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A randomised controlled trial of intravenous zoledronic acid in malignant pleural disease: a proof of principle pilot study.

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