Presently, lung cancer accounts for approximately one-third of cancer deaths, of which the vast majority of patients present or develop advanced lung cancer, and ultimately experience a rapid demise. Early trials with chemotherapy in NSCLC were quite disappointing, exhibiting a response rate of around 10-15%, and an approximate 5 week prolonged survival relative to supportive care. Moreover, in many cases chemotherapy regimens were found to be associated with worse results than supportive care alone (cyclophosphamide, methotrexate, and vinblastine). In more recent years, newer agents have been investigated that have demonstrated better median survival (1), although this median survival increased only to 7-10 months and fewer than 40% of patients remained alive at 1 year (130). As a result of these generally poor outcomes, it has been widely opined that chemotherapy in advanced lung cancer has reached a plateau, and newer approaches other than chemotherapy must be investigated (5,6). This opinion may be premature given the realization that chemotherapy for lung cancer has not been optimized using any advanced formulation or drug
Figure 4 Three-dimensional views of local particle deposition patterns around an airway tumor modeled by Kleinstreuer and Zhang. Particle deposition on the tumor surface may be influenced by the local occlusion (i.e. tumor size and location), as well as inlet velocity profile and particle distribution as a function of Reynolds number (Re) and Stokes number (St). (A-D) indicate these different flow and particle regimes. In general, particle deposition, occurring mainly along the front surface of the tumor due to impaction, increases with both increasing Stokes and Reynolds numbers. Source: From Ref. 129.
delivery approaches. Using historical experiences with asthma and cystic fibrosis as examples, major advances in disease control, life expectancy, and quality of life may be gained in lung cancer with inhalation aerosols.
While it is evident that promising results are a shared feature of the few investigations of pulmonary delivery of chemotherapy, there are numerous obstacles that remain to be satisfactorily addressed, including formulation issues due to the poor water solubility of chemotherapy agents, improving regional targeting within the airways and minimizing esophageal deposition, and controlling the absorption of chemotherapy agents subsequent to their deposition in the airways. Rapid translocation into the systemic circulation may prove pharmacokinetically beneficial for tumors located outside the respiratory tract, but may provide a significant barrier to the treatment of lung tumors, an issue that may be addressed using novel sustained pulmonary release technologies that are currently under development. Existing and novel chemotherapy agents are equally likely candidates for Phases 1 and 2 clinical trials, as evidenced by data presented in Table 1.
The successful clinical translation of pulmonary delivery systems for anti-cancer agents will necessarily require a broad spectrum of expertise, including physicians experienced in aerosol delivery studies, and aerosol drug delivery scientists to address the unique formulation and drug delivery issues of chemotherapy, ensuring that optimal targeting, stability, and pharmacokinetic profiles are attained in both preclinical models and clinical trials. With these capabilities, researchers will possess the background and expertise ideally suited to transform these promising observations into a tangible and effective treatment that will restore the hope and improve the quality of life of those unfortunate enough to be diagnosed with lung cancer. The future of inhaled chemotherapy presents a promising direction in the treatment of lung cancer; a direction that if diligently pursued may one day aid in the discovery of the cure that presently resides beyond our grasp.
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