Núria Buil-Bruna (1,2), Benjamin Ribba (2), José MarÃa López-Picazo (3), Iñaki F. Trocóniz (1)
(1) Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona 30180, Spain ; (2) INRIA Grenoble Rhône-Alpes, Numed Project Team, 38330 Montbonnot-Saint-Martin, France ;(3) Department of Oncology, University Hospital, University of Navarra, Pamplona 31008, Spain
Objectives: Lactacte dehydrogenase (LDH) is a glycolytic enzyme easily measured in blood. Previous studies have shown that pre-treatment levels of LDH have prognostic value for several solid tumours, including small cell lung cancer (SCLC)[1]. The aim of this work was to investigate whether a dynamic model for LDH longitudinal data could be used to assess clinical response in SCLC patients as an alternative to tumour size evaluation through imaging techniques.
Methods: Data included 25 patients diagnosed with extensive-stage SCLC in the University Hospital of Navarra receiving Etoposide plus either Cisplatin or Carboplatin. Typical treatment regimen included 6 chemotherapy cycles given every 3 weeks. A median of 8 concentrations per patient were included in the analysis (n total=173). Median follow-up time was 22 weeks. Clinical response was defined by ordered categorical response following RECIST criteria based on CT/SCANs. A median of 2 CT/SCANs per patient were obtained at different time points where LDH was also measured. The LDH model was developed using a non-linear mixed effect approach. Model parameters were estimated in Monolix 4.2.
Results: The model was comprised of a classic turnover model, where LDH synthesis was driven by a virtual disease compartment representing the tumour. The drug effect was characterised as an increase in the elimination rate of the disease. Resistance was modelled by linking cumulative dose to decreased drug effect (allowing for LDH increase during treatment, as observed in 52% of the patients).Despite high variability within patients, the model correctly described the individual LDH profiles. The half-life of LDH turn-over was estimated to be 20.2 hours. After two chemotherapy cycles, formation of resistance reduced drug effect by 75%. Model simulations showed that changes in LDH values were strongly correlated to observed RECIST data (p<0.001).
Conclusions: We showed that in our patient dataset, modelling LDH dynamics to predict clinical efficacy in SCLC patients can be a powerful alternative to the tumour size measurement approach. Future work will include limited-disease SCLC patients and the effect of concurrent radiotherapy.
References:
[1] Quoix E et al. Comparative prognostic value of lactate dehydrogenase and neuron-specific enolase in small-cell lung cancer patients treated with platinum-based chemotherapy. Lung Cancer 2000;30(2):127-134.
Acknowledgements: “The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement n° 115156, resources of which are composed of financial contributions from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution. The DDMoRe project is also supported by financial contribution from Academic and SME partners. This work does not necessarily represent the view of all DDMoRe partners.”
Reference: PAGE 22 (2013) Abstr 2886 [www.page-meeting.org/?abstract=2886]
Poster: Oncology