title: Early change in tumour size predicts overall survival in patients with first-line metastatic breast cancer.
abstract: Clinical trials using change in tumour size (CTS) as a primary end-point benefit from earlier evaluation of treatment effect and increased study power over progression-free survival, ultimately resulting in more timely regulatory approvals for cancer patients. In this work, a modelling framework was established to further characterise the relationship between CTS and overall survival (OS) in first-line metastatic breast cancer (mBC).
  
  
  
  Data from three randomised phase III trials designed to evaluate the clinical benefit of gemcitabine combination therapy in mBC patients were collated. Two drug-dependent models were developed to describe tumour growth dynamics: the first for paclitaxel/gemcitabine treatment and the second for docetaxel/gemcitabine treatment. A parametric survival model was used to characterise survival as a function of CTS and baseline patient demographics.
  
  
  
  While the paclitaxel/gemcitabine model incorporated tumour shrinkage by both paclitaxel and gemcitabine with resistance to paclitaxel, the docetaxel/gemcitabine model incorporated shrinkage and resistance to docetaxel alone. Predictors for OS were CTS at week 8, baseline tumour size and ECOG performance status. Model predictions reveal that for an asymptomatic mBC patient with a 6-cm tumour burden, first-line paclitaxel/gemcitabine treatment offers a median OS of 28.6 months, compared to 26.0 months for paclitaxel alone.
  
  
  
  A modelling framework was established, quantitatively describing the tumour growth inhibitory effects of various gemcitabine combotherapies and the effect of the resulting CTS on survival in first-line mBC. This work further supports the use of early CTS as a go/no-go decision point during phase II clinical evaluation of treatments for mBC.
authors.affiliation: PK/PD, Eli Lilly and Company, Erl Wood Manor, Windlesham, GU20 6PH, UK. Electronic address: tate_sonya@network.lilly.com.
authors.forename: Sonya C
authors.initials: SC
authors.lastname: Tate
authors.affiliation: Statistics, Eli Lilly and Company, Erl Wood Manor, Windlesham, GU20 6PH, UK. Electronic address: andre_valerie@lilly.com.
authors.forename: Valerie
authors.initials: V
authors.lastname: Andre
authors.affiliation: Statistics, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. Electronic address: enas_nathan_h@lilly.com.
authors.forename: Nathan
authors.initials: N
authors.lastname: Enas
authors.affiliation: Project-Team NuMed, INRIA, Ecole Normale Supérieure de Lyon, Lyon, France. Electronic address: benjamin.ribba@inria.fr.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Ribba
authors.affiliation: PK/PD, Eli Lilly and Company, Erl Wood Manor, Windlesham, GU20 6PH, UK. Electronic address: gueorguieva_ivelina@lilly.com.
authors.forename: Ivelina
authors.initials: I
authors.lastname: Gueorguieva
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D000069287:Capecitabine / Q000008:administration & dosage; D017326:Clinical Trials, Phase III as Topic; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000077143:Docetaxel; D005260:Female; D006801:Humans; D009362:Neoplasm Metastasis; D017239:Paclitaxel / Q000008:administration & dosage; D011379:Prognosis; D016032:Randomized Controlled Trials as Topic; D043823:Taxoids / Q000008:administration & dosage; D047368:Tumor Burden / Q000187:drug effects; D000093542:Gemcitabine
chemical_list: D043823:Taxoids; D003841:Deoxycytidine; D000077143:Docetaxel; D000069287:Capecitabine; D017239:Paclitaxel; D000093542:Gemcitabine
keywords: Breast cancer; Capecitabine; Docetaxel; Gemcitabine; Mathematical model; Paclitaxel; Response evaluation criteria in solid tumours; Survival analysis; Treatment outcome