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

Abstract

IntroductionAnimal 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.MethodsWe 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.ResultsBetween 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.ConclusionsThis 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 RegistrationUK Clinical Research Network ID 8877 ISRCTN17030426 www.isrctn.com

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“…[163][164][165] However, there are also multiple randomised trials that have failed to demonstrate improvement in non-bone related outcomes. [166][167][168][169][170][171][172][173] Overall, it has not been apparent that NBPs have substantial anti-cancer activities outside of the setting of bone marrow/bone disease, which is likely a consequence of their limited systemic distribution due to their high bone affinity. 174,175…”

“…Several studies have suggested more direct anti‐tumour activity of zoledronic acid in the setting of breast cancer where enhanced tumour cell apoptosis or clearance of bone marrow disseminated tumour cells have been observed 163–165 . However, there are also multiple randomised trials that have failed to demonstrate improvement in non‐bone related outcomes 166–173 . Overall, it has not been apparent that NBPs have substantial anti‐cancer activities outside of the setting of bone marrow/bone disease, which is likely a consequence of their limited systemic distribution due to their high bone affinity 174,175 …”

What can independent research for mesothelioma achieve to treat this orphan disease?

“…Among eight pretreated patients, the median PFS was 2 months and the median OS was 7 months without significant toxicity. Another study by Clive et al [105], looking at the role of Zol in malignant pleural effusions, showing that two patients with MPM had a reduction in tumour bulk on radiology after receiving two doses of ZA intravenously. A recent multicentre double-blind randomised controlled feasibility study aims to assess the recruitment and acceptability of Zol/placebo alongside chemotherapy in MPM [106].…”

18F-Fluorodeoxyglucose PET/CT and dynamic contrast-enhanced MRI as imaging biomarkers in malignant pleural mesothelioma

“…A method for Region of Interest (ROI) definition was developed, based on Giesel et al [6,7]. A similar method has been described for a study of Zoledronic acid in pleural disease [8]. The tumor was identified on the T1 image ( figure 1A), taking account of the enhancement image by a consensus of two radiologists experienced in DCE-MRI analysis.…”