A pilot study of zoledronic acid in the treatment of patients with advanced malignant pleural mesothelioma

Abstract

PurposeMalignant 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 methodsWe 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.ResultsEight 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.ConclusionZoledronic acid shows modest clinical activity without significant toxicity in patients with advanced MPM.

Drug repurposing in malignant pleural mesothelioma: a breath of fresh air?

“…Among eight pretreated patients, the median PFS was 2 months and the median OS was 7 months without significant toxicity. In this study, a decrease of VEGF level was predictive of favourable response [96].…”

“…Osteoporosis, hypercalcaemia [91] Inhibition of cell proliferation Inhibition of invasion Inhibition of angiogenesis Inhibition of bone metastases Immunomodulatory function [92,93] Reversion of chemoresistance [94] Phase III: breast cancer [95] Phase II [96] HDAC: histone deacetylase inhibitor; SCLC: small cell lung cancer; NSCLC: nonsmall cell lung cancer; FDA: United States Food and Drug Administration; NSAIDs: nonsteroidal anti-inflammatory drugs; EMT: epithelial-mesenchymal transition.…”

New Horizons from Novel Therapies in Malignant Pleural Mesothelioma

“…A recent study demonstrated that zoledronic acid can potentially aid in restoring immune reactivity and chemosensitivity in MPM by decreasing RAS/ERK activity [44]. A single-arm clinical trial carried out in www.journals.viamedica.pl 8 patients with advanced MPM showed modest clinical activity and no significant toxic effects in patients who received zoledronic acid [45]. An in vivo microenvironment study showed that Pirfenidone can decrease proliferation and migration of MPM cells by causing inhibition of ERK [46].…”

Zoledronic acid in the management of mesothelioma - a feasibility study (Zol-A Trial): study protocol for a randomised controlled trial

“…A study by Jamil et al [ 12 ] recently investigated the role of single agent ZA in a small cohort of patients with MPM who have either completed chemotherapy or were too frail to receive chemotherapy. They demonstrated some benefit with ZA, where there was a 37.5% rate of clinical benefit (progression-free survival and stable disease).…”