CURRENT STATUS OF INHALED CHEMOTHERAPY FOR LUNG CANCER文献综述

BILAL, ABDULRAHMAN SAID GHARIB

154301030

PROFESSOR XUE, HONG

SCHOOL OF CLINICAL PHARMACY

CURRENT STATUS OF INHALED CHEMOTHERAPY FOR LUNG CANCER

Abstract: Despite new treatment modalities, including targeted therapies and checkpoint inhibitors, cytotoxic chemotherapy remains central in the care of patients with lung tumors. Use of the pulmonary route to deliver chemotherapy has been proved to be feasible and safe in phase I, Ib/IIa and II trials for lung tumors, with the administration of drug doses to the lungs without prior distribution in the organism. The severe systemic toxicities commonly observed with conventional systemic chemotherapy are consequently reduced. However, development has failed in phase II at best. This review first focuses on the causes of failure of inhaled chemotherapy. It then presents new promising technologies able to take up the current challenges. These technologies include the use of a dry powder inhaler or a smart nebulizer with advanced drug formulations such as controlled-release formulations and nanomedicine. Finally, the potential position of inhaled chemotherapy in patient care is discussed and some indications are proposed based on the literature.

Introduction

Chemotherapy remains the backbone of the care of patients with lung tumors, including advanced primary tumors and lung metastases. This is despite severe systemic toxicities that are due to chemotherapyrsquo;s poor selectivity for tumor cells compared to normal cells and the use of systemic routes of administration, i.e., mainly the intravenous (iv) route, which results in a distribution of the drug to the entire organism. To decrease these toxicities, the use of the pulmonary route is promising. Pulmonary drug delivery is well-established for treating many respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD) . Compared with systemic delivery (i.e., through enteral and parenteral routes), pulmonary delivery allows high local drug concentrations and low systemic exposure, i.e., it increases the therapeutic ratio. In theory, this approach should therefore be highly beneficial in the care of patients with lung tumors.

The first clinical report on inhaled chemotherapy was published in 1968 . Since then, many clinical trials have been conducted in different populations of patients with lung cancer or lung metastases. Although inhaled chemotherapy has been proved to be feasible and safe in mostof these trials, all the products involved have failed in phase II at best . This narrative review first focuses on the main causes of failure of inhaled chemotherapy in clinical trials. Key clinical reports are discussed. Then, alternative approaches and new technologies that are undergoing preclinical research are reviewed. Finally, the possible position of inhaled chemotherapy in patient care is discussed and potential indications are suggested. It must be noted that the present review only focuses on inhaled chemotherapy. It does not include inhaled therapies such as inhaled gene therapy or immunotherapy, although these are also promising.

Inhaled Chemotherapy in Clinical Trials: What Are the Causes of Failure?