title: Mathematical optimisation of the cisplatin plus etoposide combination for managing extensive-stage small-cell lung cancer patients.
abstract: 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.
  
  
  
  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.
  
  
  
  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-2over 1 h D1, followed by a long infusion 12 h later (over 3 days) of 160 mg m-2plus cisplatin 80 mg m-2over 1 h D1, D1-D1 21 days; (2) Protocol OP2: etoposide 80 mg m-2over 1 h D1, followed by a long infusion 12 h later (over 4 days) of 300 mg m-2plus cisplatin 100 mg m-2over 1 h D1, D1-D1 21 days; and (3) Protocol OP3: etoposide 40 mg m-2over 1 h, followed by a long infusion 6 h later (3 days) of 105 mg m-2plus cisplatin 50 mg m-2over 1 h, D1-D1 14 days.
  
  
  
  Mathematical modelling can help optimise the design of new cisplatin plus etoposide regimens for managing extensive-stage SCLC patients.
authors.affiliation: Aix Marseille Université, Inserm S_911 CRO2, SMARTc, Marseille, France.
authors.forename: C
authors.initials: C
authors.lastname: Faivre
authors.affiliation: Aix Marseille Université, Inserm S_911 CRO2, SMARTc, Marseille, France.
authors.forename: R
authors.initials: R
authors.lastname: El Cheikh
authors.affiliation: Aix Marseille Université, Inserm S_911 CRO2, SMARTc, Marseille, France.
authors.forename: D
authors.initials: D
authors.lastname: Barbolosi
authors.affiliation: Aix Marseille Université, Inserm S_911 CRO2, SMARTc, Marseille, France.|Aix Marseille Université, Assistance Publique Hôpitaux de Marseille, Multidisciplinary Oncology and Therapeutic Innovations dpt, 13915 Marseille Cedex 20, France.
authors.forename: F
authors.initials: F
authors.lastname: Barlesi
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002138:Calibration; D002945:Cisplatin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D018450:Disease Progression; D054796:Drug Dosage Calculations; D005047:Etoposide / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D008962:Models, Theoretical; D009367:Neoplasm Staging; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D005047:Etoposide; D002945:Cisplatin