Mathematical optimisation of the cisplatin plus etoposide combination for managing extensive-stage small-cell lung cancer patients

Background: Small-cell lung cancer (SCLC) represents one of the most aggressive forms of lung cancer. Despite the fair sensitivity of SCLC to chemotherapy and radiotherapy, the current standard treatment regimens have modest survival rates and are associated with potential life-threatening adverse events. Therefore, research into new optimised regimens that increase drug efficacy while respecting toxicity constraints is of primary importance. Methods: A PK/PD model for the combination of cisplatin and etoposide to treat extensive-stage SCLC patients was generated. The model takes into consideration both the efficacy of the drugs and their haematological toxicity. Using optimisation techniques, the model can be used to propose new regimens. Results: Three new regimens with varying timing for combining cisplatin and etoposide have been generated that respect haematological toxicity constraints and achieve better or similar tumour regression. The proposed regimens are: (1) Protocol OP1: etoposide 80 mg m^-2 over 1 h D1, followed by a long infusion 12 h later (over 3 days) of 160 mg m^-2 plus cisplatin 80 mg m^-2 over 1 h D1, D1-D1 21 days; (2) Protocol OP2: etoposide 80 mg m^-2 over 1 h D1, followed by a long infusion 12 h later (over 4 days) of 300 mg m^-2 plus cisplatin 100 mg m^-2 over 1 h D1, D1-D1 21 days; and (3) Protocol OP3: etoposide 40 mg m^-2 over 1 h, followed by a long infusion 6 h later (3 days) of 105 mg m^-2 plus cisplatin 50 mg m^-2 over 1 h, D1-D1 14 days. Conclusions: Mathematical modelling can help optimise the design of new cisplatin plus etoposide regimens for managing extensive-stage SCLC patients.