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

Our plain-English summary of A pilot study of zoledronic acid in the treatment of patients with advanced malignant pleural mesothelioma, by M.O. Jamil, M.S. Jerome, D. Miley, et al (Lung Cancer, 2017).

The study

• Authors: M.O. Jamil, M.S. Jerome, D. Miley, K.S. Selander, F. Robert
• Journal: Lung Cancer
• Published: 2017;8:39-44
• Cited by: 11 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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.

In plain English

This pilot study at the University of Alabama at Birmingham Comprehensive Cancer Center tested zoledronic acid, an osteoporosis drug, in adults with advanced malignant pleural mesothelioma that could not be removed by surgery. It had a single treatment group and no comparison group. Between November 2010 and January 2015, 9 patients consented and 8 were treated. All 8 were men, with a median age of 62, and all except 2 reported a history of asbestos exposure. Patients received 4 mg of zoledronic acid by intravenous infusion every 3 weeks. No patient responded by modified RECIST CT criteria. When PET scan results were also counted, the overall response rate was 12.5% and the rate of response plus stable disease was 37.5%. Median time without progression was 2 months and median survival was 7 months. No treatment-related side effects were observed. Patients who did not respond had higher starting blood levels of VEGF and osteopontin. The authors concluded that their pilot study suggests modest activity of zoledronic acid as a single drug and warrants further study in combination with other agents.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Single-arm, prospective pilot (proof-of-concept feasibility) treatment study, using descriptive statistics only
• Who was studied: 8 treated patients (9 consented) with unresectable, advanced malignant pleural mesothelioma at the University of Alabama at Birmingham, November 2010 to January 2015. All were male (7 Caucasian, 1 African-American), median age 62 (range 49 to 77), and 6 had epithelioid mesothelioma. 3 were treatment naive and the others had received one or more lines of chemotherapy. All except 2 reported a history of asbestos exposure.
• Exposure: The exposure studied was treatment with zoledronic acid, 4 mg intravenously over 15 minutes on day 1 of each 3-week cycle, continued until progression or intolerable toxicity. Asbestos exposure was recorded only as patient history; no fiber types are given.
• Main results:
  • By modified RECIST CT criteria, no patient responded and 2 patients had a best response of stable disease, one lasting 21 months
  • Among the 8 treated patients, the composite response rate (CT plus PET) was 12.5% and the clinical benefit rate (response plus stable disease) was 37.5%
  • Median progression-free survival was 2 months (range 0.5 to 21 months) and median overall survival was 7 months (range 0.8 to 28 months)
  • No treatment-related toxicities were observed
  • Nonresponders had higher baseline VEGF and osteopontin levels (mean baseline VEGF 190.6 pg/mL in nonresponders vs 48.7 pg/mL in responders). The authors reported decreasing mesothelin and osteopontin levels in patients with response or stable disease.
  • No association with disease burden or progression was seen for IL-8, bFGF or TGF-beta
• The authors' conclusion: The authors concluded that their pilot study suggests modest activity of zoledronic acid as a single agent in mesothelioma, and that this warrants further investigation in combination with other agents.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Median Overall Survival, Chemotherapy, Mesothelioma, Angiogenesis, Apoptosis, Performance Status, Systemic Therapy.

Related studies

• Zoledronic acid impairs myeloid differentiation to tumour-associated macrophages in mesothelioma — J.D. Veltman, M.E. Lambers, et al. (2010)
• Zoledronic acid induces apoptosis and S-phase arrest in mesothelioma through inhibiting Rab family proteins and topoisomerase II actions — S. Okamoto, Y. Jiang, et al. (2014)
• Zoledronic acid overcomes chemoresistance and immunosuppression of malignant mesothelioma — I.C. Salaroglio, I. Campia, et al. (2015)
• Zoledronic acid produces antitumor effects on mesothelioma through apoptosis and S-phase arrest in p53-independent and Ras prenylation-independent manners — S. Okamoto, K. Kawamura, et al. (2012)
• Zoledronic acid produces combinatory anti-tumor effects with cisplatin on mesothelioma by increasing p53 expression levels — S. Okamoto, Y. Jiang, et al. (2013)
• An intrapleural administration of zoledronic acid for inoperable malignant mesothelioma patients: a phase I clinical study protocol — Y. Tada, K. Hiroshima, et al. (2016)

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