Pulmonary and renal tolerance of cisplatin-based regimens combining intravenous and endotracheal routes for lung cancer treatment in mice

Despite recent advances, platinum-based chemotherapy (partially composed of cisplatin, CIS) remains the backbone of non-small-cell lung cancer treatment. As CIS presents a cumulative and dose-limiting nephrotoxicity, it is currently administered with an interruption phase of 3-4 weeks between treatment cycles. During these periods, the patient recovers from the treatment side effects but so does the tumour. Our strategy is to increase the treatment frequency by delivering a cisplatin controlled-release dry powder for inhalation (CIS-DPI) formulation during these off-cycles to expose the tumour environment for longer to CIS, increasing its effectiveness. This is promising as long as the pulmonary and renal toxicities remain acceptable. The aim of the present investigation was to evaluate the pulmonary and renal tolerance of CIS-DPI (three times per cycle) and CIS using the intravenous (IV) route (CIS-IV) (one time per cycle) as monotherapies and to optimize their combination in terms of dose and schedule. At the maximum tolerated dose (MTD), combining CIS-DPI and CIS-IV impaired the pulmonary and the renal tolerance. Therefore, pulmonary tolerance was improved when the CIS-IV dose was decreased by 25% (to 1.5 mg/kg) while maintaining the MTD for CIS-DPI. In addition to this dose adjustment, a delay of 24 h between CIS-DPI and CIS-IV administrations limited the acute kidney injury.

Automated summary

The study aimed to evaluate the pulmonary and renal tolerance of cisplatin controlled-release dry powder for inhalation (CIS-DPI) and intravenous cisplatin (CIS-IV) as monotherapies, and to optimize their combination in terms of dose and schedule. Combining CIS-DPI and CIS-IV at the maximum tolerated dose impaired pulmonary and renal tolerance. However, improving pulmonary tolerance was achieved by decreasing the CIS-IV dose by 25% while maintaining the MTD for CIS-DPI, along with a 24-hour delay between CIS-DPI and CIS-IV administrations to limit acute kidney injury.