An intrapleural administration of zoledronic acid for inoperable malignant mesothelioma patients: a phase I clinical study protocol

Our plain-English summary of An intrapleural administration of zoledronic acid for inoperable malignant mesothelioma patients: a phase I clinical study protocol, by Y. Tada, K. Hiroshima, H. Shimada, et al (SpringerPlus, 2016).

The study

• Authors: Y. Tada, K. Hiroshima, H. Shimada, M. Shingyoji, T. Suzuki, H. Umezawa, I. Sekine, Y. Takiguchi, K. Tatsumi, M. Tagawa
• Journal: SpringerPlus
• Published: 2016;5:195
• Cited by: 8 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: The third generation of bisphosphonates is clinically in use for patients of osteoporosis or malignancy-linked hypercalcemia. The agents can also produce anti-tumor effects on bone metastasis of several types of tumors. We recently found that one of the agents achieved cytotoxicity to mesothelioma in vitro and in an orthotopic animal model. Mesothelioma is resistant to a number of chemotherapeutic agents, and suppression of local tumor growth is beneficial to the patients since metastasis to extra-thoracic organs is relatively infrequent until a late stage.

Methods/design: We demonstrated in an orthotopic mouse model that an intrapleural but not intravenous injection of zoledronic acid, one of the third generation bisphosphonates, at a clinically equivalent dose suppressed the tumor growth. Nevertheless, a high concentration of zoledronic acid administrated in the pleural cavity produced pleural adhesion. We also showed that zoledronic acid produced synergistic cytotoxic effects with cisplatin, the first-line chemotherapeutic agent for mesothelioma. We then planned to conduct a phase I clinical study to investigate any adverse effects and a possible clinical benefits produced by an intrapleural administration of zoledronic acid to mesothelioma patients who became resistant to the first-line chemotherapeutic agents. The clinical trial is a dose escalation study starting with 0.4, 1, 4, 8 and 16 mg per person since safety of administration of zoledronic acid into the pleural cavity remains unknown. Each dose group consists of three persons and the protocol allows to repeat administration of the same dose into the pleural cavity at a 4-weeks interval.

Discussion: We will conduct a possible combinatory study of intrapleural administration of zoledronic acid and systemic administration of the first-line agent to a chemotherapy-naïve patient based on the maximum tolerance dose of zoledronic acid determined by the present clinical trial. We propose that administration of bisphosphonates in a closed cavity is a treatment strategy for tumors developed in the cavity probably through the direct cytotoxic activity.

Trial Registration: UMIN clinical trials registry, Japan. Register ID: UMIN8093.

In plain English

This article was a study protocol. It described a planned phase I trial at Chiba University Hospital, Japan, and reported no patient results. Zoledronic acid, a bisphosphonate drug, was to be injected into the chest cavity of people with malignant pleural mesothelioma who were unsuitable for or declined surgery, and who were refractory to or declined chemotherapy. Doses were to rise from 0.4 to 16 mg. Each dose group would have three patients, or six if one had a side effect above grade 3, so that the maximum tolerated dose could be defined. The authors also reported experiments in nude mice with human mesothelioma cells placed in the chest. Injected into the chest, the drug reduced tumor growth in a dose-dependent way. In one experiment, average tumor weight at day 28 was 384.8 mg with saline and 19.8 mg with 40 μg of the drug. Given into the abdomen, it did not significantly change the growth of tumors under the skin. An 80 μg dose caused pleura-pericardium adhesions in most mice, and 40 μg did not. The authors concluded that the usual clinical dose, injected into a chest containing fluid, could produce anti-tumor effects.

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: Study protocol for a phase I dose-escalation clinical trial, together with preclinical mouse experiments reported in the article
• Who was studied: Planned trial: patients aged 20 to 80 with pathologically diagnosed malignant pleural mesothelioma (locally advanced or recurrent). Eligible patients are not suitable for surgery or refuse it irrespective of clinical stage, and are refractory to or decline chemotherapy. They must have pleural effusion and ECOG performance status 0 to 2. The trial is at Chiba University Hospital, Japan, with three patients per dose group, expanded to six if one patient has an adverse effect greater than grade 3. Preclinical: BALB/c nude mice inoculated in the chest with human mesothelioma cells (MSTO-211H or EHMES-10), 5 to 7 mice per experiment.
• Exposure: Not an asbestos exposure study. The intervention is zoledronic acid (ZOL) injected into the pleural cavity in 100 ml saline, at escalating single doses per person, repeatable at the same dose every 4 weeks. Mice received 15, 40 or 80 μg ZOL into the chest, or 15 or 50 μg into the abdomen.
• Main results:
  • In mice, ZOL injected into the chest suppressed tumor growth in a dose-dependent way, whichever mesothelioma cell line was used.
  • Experiment 1 (MSTO-211H cells, day 28, n = 5): average tumor weight was 491.1 ± 68.4 mg with saline (PBS) and 0 with 80 μg ZOL (P < 0.01).
  • Experiment 2 (MSTO-211H cells, day 28, n = 6): average tumor weight was 384.8 ± 36.8 mg with PBS and 19.8 ± 7.2 mg with 40 μg ZOL (P < 0.01).
  • Experiment 3 (EHMES-10 cells, day 35, n = 7): average tumor weight was 197.7 ± 22.9 mg with PBS, 2.5 ± 1.2 mg with 40 μg ZOL and 79.3 ± 13.2 mg with 15 μg ZOL (P < 0.01).
  • Experiment 4 (MSTO-211H cells, drug given on day 10, assessed day 28, n = 7): average tumor weight was 377.9 ± 13.3 mg with PBS and 188.6 ± 62.1 mg with 40 μg ZOL (P < 0.05).
  • In mice given ZOL into the abdominal cavity (15 or 50 μg), subcutaneous tumor volumes were not statistically different from PBS at any time (n = 6).
  • In mice, 80 μg ZOL in the chest caused adhesion between pleura and pericardium in most animals. The authors reported that 40 μg did not.
  • Heart weights rose in mice given 40 μg ZOL in experiment 2 at day 28 (114.5 ± 3.6 mg vs 99.8 ± 5.2 mg with PBS). This mild cardiomegaly was not detected at day 35 in experiment 3.
  • In mice given 40 μg ZOL, pleura and the tissues beneath it showed no cellular infiltration under the microscope.
• The authors' conclusion: The authors concluded that the current clinical dose of ZOL, injected into the pleural cavity of a patient with pleural effusion, could produce anti-tumor effects. The planned trial is meant to evaluate its safety and efficacy.
• Limitations the authors state:
  • The ZOL concentration in the pleural cavity is difficult to estimate because the volume of pleural effusion is hard to assess.
  • Tissue distribution of ZOL cannot be measured because no enzyme-linked immunosorbent assay for ZOL is available.
  • The study will not take histological subtype into account because few patients are enrolled.
  • The study will not investigate activation of γδ T cells, because detecting them requires careful examination.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Metastasis, Pleural Cavity, Cisplatin, Clinical Trial, Chemotherapy.

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