title: An intrapleural administration of zoledronic acid for inoperable malignant mesothelioma patients: a phase I clinical study protocol.
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
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  UMIN clinical trials registry, Japan. Register ID: UMIN8093.
authors.affiliation: Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Tada
authors.affiliation: Department of Pathology, Tokyo Women's Medical University Yachiyo Medical Center, Yachiyo, Japan.
authors.forename: Kenzo
authors.initials: K
authors.lastname: Hiroshima
authors.affiliation: Department of Surgery, School of Medicine, Toho University, Tokyo, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Shimada
authors.affiliation: Division of Respirology, Chiba Cancer Center, Chiba, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Shingyoji
authors.affiliation: Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Umezawa
authors.affiliation: Department of Medical Oncology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Sekine
authors.affiliation: Department of Medical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Takiguchi
authors.affiliation: Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Tatsumi
authors.affiliation: Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuo-ku, Chiba, 260-8717 Japan ; Department of Molecular Biology and Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Tagawa
keywords: Bisphosphonates; Chemotherapy; Clinical study; Mesothelioma; Pleural cavity