title: Metabolic and molecular relative percentage coreduction in patients with locally advanced rectal cancer treated with neoadjuvant therapy.
abstract: OBJECTIVE
  Vascular endothelial growth factor receptor-2 (VEGFR-2), epidermal growth factor receptor-1 (EGFR) and cyclooxygenase-2 (COX-2) stimulate key processes involved in tumour progression and are important targets for cancer therapeutics. (18)F-FDG maximum standardized uptake value (SUVmax) on PET/CT is a marker of tumour metabolic activity. The purpose of this study was to measure percentage reductions in SUVmax (∆SUVmax%), VEGFR-2 (∆VEGFR-2%), EGFR (∆EGFR%) and COX-2 (∆COX-2%) in patients with locally advanced rectal cancer (LARC) after preoperative treatment, and to correlate the changes in these markers of response with pathological response in terms of tumour regression grade (TRG) using Rödel's scale and long-term clinical outcome.
  
  
  METHODS
  VEGFR-2, EGFR and COX-2 were measured using a quantitative and qualitative compound immunohistochemistry analysis (immunoreactive score) of the pretreatment endoscopic biopsy and definitive surgical specimens. Composite indexes using ∆SUVmax% and the three molecules were developed to differentiate patients with metabolic and molecular responses from nonresponders. Cox proportional hazards model was used to explore associations between the tumour markers, disease-free survival (DFS) and overall survival (OS).
  
  
  RESULTS
  The analysis included 38 patients with a median follow-up of 86 months (range 5 - 113 months). The ∆VEGFR-2%/∆SUVmax% index correctly identified 13 of 19 pathological responders (TRG 3 and 4) and 17 of 19 nonresponders (TRG 0 - 2) (sensitivity 68 %, specificity 89 %, accuracy 79 %, positive predictive value 87 %, negative predictive value 74 %). In multivariate analysis, only the ∆VEGFR-2%/∆SUVmax% index was associated with DFS (HR 0.11, p = 0.001) and OS (HR 0.15, p = 0.02).
  
  
  CONCLUSIONS
  In patients with LARC the ∆VEGFR-2%/∆SUVmax% response index is associated with outcome. Determination of the optimal diagnostic cut-off level for this novel biomarker association should be explored. Evaluation in a clinical trial is required to determine whether selected patients could benefit from treatment with a VEGFR-targeted therapeutic agent.
authors.affiliation: Department of Radiation Oncology, Instituto de Radiomedicina, Santiago, Chile.|Institute for Sanitary Research, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
authors.forename: Claudio V
authors.initials: CV
authors.lastname: Sole
authors.affiliation: Institute for Sanitary Research, Hospital General Universitario Gregorio Marañón, Madrid, Spain. cvsole@hotmail.com.|Department of Oncology, Hospital General Universitario Gregorio Marañón, Madrid, Spain. cvsole@hotmail.com.|School of Medicine Complutense University, Madrid, Spain. cvsole@hotmail.com.
authors.forename: Felipe A
authors.initials: FA
authors.lastname: Calvo
authors.affiliation: Institute for Sanitary Research, Hospital General Universitario Gregorio Marañón, Madrid, Spain.|School of Medicine Complutense University, Madrid, Spain.|Department of Pathology, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
authors.forename: Emilio
authors.initials: E
authors.lastname: Alvarez
authors.affiliation: Institute for Sanitary Research, Hospital General Universitario Gregorio Marañón, Madrid, Spain.|School of Medicine Complutense University, Madrid, Spain.|Department of Radiology and Medical Physics, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Carreras
mesh_terms: D000328:Adult; D000368:Aged; D051546:Cyclooxygenase 2 / Q000378:metabolism; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D000072078:Positron Emission Tomography Computed Tomography; D012004:Rectal Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D016896:Treatment Outcome; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D051546:Cyclooxygenase 2; C512478:EGFR protein, human; D066246:ErbB Receptors; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: 18F-FDG PET/CT SUVmax; Locally advanced rectal cancer; Long-term outcomes; Neoadjuvant chemoradiotherapy; VEGFR-2