title: Effects of erlotinib therapy on [(11)C]erlotinib uptake in EGFR mutated, advanced NSCLC.
abstract: BACKGROUND
  In non-small cell lung cancer (NSCLC) patients off erlotinib therapy, positron emission tomography (PET) using [(11)C]erlotinib distinguished epidermal growth factor receptor (EGFR) mutations from wild-type EGFR. However, tumor uptake of [(11)C]erlotinib during erlotinib therapy is unknown. Therefore, the aims of this study were to evaluate tumor [(11)C]erlotinib uptake in NSCLC patients both on and off erlotinib therapy, to evaluate the effect of erlotinib therapy on tumor perfusion and its correlation to tumor [(11)C]erlotinib uptake, and also, to investigate simplified uptake parameters using arterial and venous blood samples.
  
  
  METHODS
  Ten patients were to be scanned twice with a 1-2-week interval, i.e., on (E+) and off (E-) erlotinib therapy. Each procedure consisted of a low-dose CT scan, a 10-min dynamic [(15)O]H2O PET scan, and a 60-min dynamic [(11)C]erlotinib PET scan with arterial and venous sampling at six time points. In patients(E+), the optimal compartment model was analyzed using Akaike information criterion. In patients(E-), the uptake parameter was the volume of distribution (V T), estimated by using metabolite-corrected plasma input curves based on image-derived input functions and discrete arterial and venous blood samples. Tumor blood flow (TBF) was determined by rate constant of influx (K1) of [(15)O]H2O using the 1T2k model and correlated with V T and K1 values of [(11)C]erlotinib. The investigated simplified parameters were standardized uptake value (SUV) and tumor-to-blood ratio (TBR) at 40-60 min pi interval.
  
  
  RESULTS
  Of the 13 patients included, ten were scanned twice. In patients(E+), [(11)C]erlotinib best fitted the 2T4k model with V T. In all patients, tumor V T(E+) was lower than V T(E-) (median V T(E-) = 1.61, range 0.77-3.01; median V T(E+) = 1.17, range 0.53-1.74; P = 0.004). Using [(15)O]H2O, five patients were scanned twice. TBF did not change with erlotinib therapy, TBF showed a positive trend towards correlation with [(11)C]erlotinib K1, but not with V T. TBR40-50 and TBR50-60, using both arterial and venous sampling, correlated with V T(E-) (all r s >0.9, P < 0.001), while SUV did not. In patients off and on therapy, venous TBR underestimated arterial TBR by 26 ± 12 and 9 ± 9 %, respectively.
  
  
  CONCLUSIONS
  In patients on erlotinib in therapeutic dose, tumor V T decreases with high variability, independent of tumor perfusion. For simplification of [(11)C]erlotinib PET scanning protocols, both arterial and venous TBR 40-60 min post injection can be used; however, arterial and venous TBR values should not be interchanged as venous values underestimate arterial values.
  
  
  BACKGROUND
  Registered at the Netherlands Trial Registry: NTR3670 .
authors: Department of Pulmonary Diseases, VU University Medical Center, PO Box 7057, 1007MB, Amsterdam, The Netherlands. i.bahce@vumc.nl.
authors: Idris
authors: I
authors: Bahce
authors: Department of Radiology & Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands.
authors: Maqsood
authors: M
authors: Yaqub
authors: Department of Pulmonary Diseases, VU University Medical Center, PO Box 7057, 1007MB, Amsterdam, The Netherlands.
authors: Hanane
authors: H
authors: Errami
authors: Department of Radiology & Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands.
authors: Robert C
authors: RC
authors: Schuit
authors: Department of Anesthesiology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Patrick
authors: P
authors: Schober
authors: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Erik
authors: E
authors: Thunnissen
authors: Department of Radiology & Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands.
authors: Albert D
authors: AD
authors: Windhorst
authors: Department of Radiology & Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands.
authors: Adriaan A
authors: AA
authors: Lammertsma
authors: Department of Pulmonary Diseases, VU University Medical Center, PO Box 7057, 1007MB, Amsterdam, The Netherlands.|Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors: Egbert F
authors: EF
authors: Smit
authors: Department of Radiology & Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands.|Department of Clinical Pharmacology & Pharmacy, VU University Medical Center, Amsterdam, The Netherlands.
authors: N Harry
authors: NH
authors: Hendrikse
keywords: Erlotinib therapy; NSCLC; PET; [11C]Erlotinib