A phase I trial evaluated the feasibility and safety of inhaled 9-NC in the treatment of patients with primary or metastatic lung cancer (Verschraegen et al. 2004). 9-NC was administered on days 1-5 every week for a period of 6 weeks. The MTD was 20 pg/kg/day, but a lower-dose level of 13.3 pg/kg/day was well tolerated. Two patients with metastatic endometrial cancer had partial response to treatment, and the treatment benefit was not confined to the lung tumors (Verschraegen et al. 2004). Overall, inhaled 9-NC was found to be well tolerated with an acceptable safety profile; however, no further clinical development of this formulation has been reported.
Cisplatin and carboplatin are the primary treatment agents used in several combination chemotherapy regimens for systemic treatment of lung cancer. The safety of inhaled cisplatin encapsulated in microscopic phospholipid spheres or sustained- release lipid inhalation targeting (SLIT)™ was evaluated in a phase I study by Wittgen and colleagues (2007). The treatment was well tolerated, and the serum levels of cisplatin varied between low to undetectable in most cases. No treatment response was reported, but 12 of 17 patients were reported to have stable disease at the time of evaluation (Zarogoulidis et al. 2012). Cisplatin lipid complex was also evaluated in the treatment of 19 pediatric patients with pulmonary metastases from recurrent osteosarcoma in a phase I/II study (Chou et al. 2013). In the eight patients with nonbulky disease (size of lesions <2 cm), one had partial response and two patients had stable disease. Because dose-limiting toxicity was not reported in the clinical trials reported with SLIT™ (Wittgen et al. 2007; Chou et al. 2013), further studies would be needed to determine if the efficacy of treatment could be improved with higher doses or use of alternative formulations of cisplatin.
Carboplatin is frequently used in the frontline treatment of advanced-stage NSCLC. Inhaled carboplatin in the treatment of NSCLC was evaluated in a small trial (Zarogoulidis et al. 2012). In this trial, 60 patients with advanced-stage NSCLC were randomized into 3 groups. The first group received IV carbopla- tin and docetaxel (control arm), whereas the second group received IV docetaxel, two-thirds of the calculated carboplatin IV, and one-third carboplatin dose as an inhalant. The third group received the entire dose of carboplatin administered in the aerosol form along with IV docetaxel. Patients receiving both IV and inhaled carboplatin (group 2) had better survival outcomes compared to the control arm— 275 days versus 211 days (Zarogoulidis et al. 2012). There was a trend toward improvement in the median overall survival for patients receiving inhaled carbo- platin with IV docetaxel.
The development of resistance to chemotherapeutic agents is a frequent cause of treatment failure and tumor recurrence. Several approaches to reduce the development of resistance, such as adding pump and nonpump suppressors to inhaled chemotherapy (Hohenforsdt-Schmidt et al. 2014) or combining an active agent with an appropriate drug carrier that can specifically target sites in the respiratory tract where drug transporter genes are highly expressed or combining inhaled chemotherapy and gene therapy (Taratula et al. 2013), are currently under investigation.