title: The Prognostic Significance of Metabolic Response Heterogeneity in Metastatic Colorectal Cancer.
abstract: BACKGROUND
  Tumoral heterogeneity is a major determinant of resistance in solid tumors. FDG-PET/CT can identify early during chemotherapy non-responsive lesions within the whole body tumor load. This prospective multicentric proof-of-concept study explores intra-individual metabolic response (mR) heterogeneity as a treatment efficacy biomarker in chemorefractory metastatic colorectal cancer (mCRC).
  
  
  METHODS
  Standardized FDG-PET/CT was performed at baseline and after the first cycle of combined sorafenib (600mg/day for 21 days, then 800mg/day) and capecitabine (1700 mg/m²/day administered D1-14 every 21 days). MR assessment was categorized according to the proportion of metabolically non-responding (non-mR) lesions (stable FDG uptake with SUVmax decrease <15%) among all measurable lesions.
  
  
  RESULTS
  Ninety-two patients were included. The median overall survival (OS) and progression-free survival (PFS) were 8.2 months (95% CI: 6.8-10.5) and 4.2 months (95% CI: 3.4-4.8) respectively. In the 79 assessable patients, early PET-CT showed no metabolically refractory lesion in 47%, a heterogeneous mR with at least one non-mR lesion in 32%, and a consistent non-mR or early disease progression in 21%. On exploratory analysis, patients without any non-mR lesion showed a significantly longer PFS (HR 0.34; 95% CI: 0.21-0.56, P-value <0.001) and OS (HR 0.58; 95% CI: 0.36-0.92, P-value 0.02) compared to the other patients. The proportion of non-mR lesions within the tumor load did not impact PFS/OS.
  
  
  CONCLUSIONS
  The presence of at least one metabolically refractory lesion is associated with a poorer outcome in advanced mCRC patients treated with combined sorafenib-capecitabine. Early detection of treatment-induced mR heterogeneity may represent an important predictive efficacy biomarker in mCRC.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01290926.
authors.affiliation: Medical Oncology Department, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Alain
authors.initials: A
authors.lastname: Hendlisz
authors.affiliation: Medical Oncology Department, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Amelie
authors.initials: A
authors.lastname: Deleporte
authors.affiliation: Oncology Department, Jolimont Hospital, Haine-St-Paul, Belgium.
authors.forename: Thierry
authors.initials: T
authors.lastname: Delaunoit
authors.affiliation: Gastroenterology Medico-Surgical Department, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Maréchal
authors.affiliation: Oncology Department, Antwerp University Hospital, Antwerp University, Edegem, Belgium.
authors.forename: Marc
authors.initials: M
authors.lastname: Peeters
authors.affiliation: Oncology Department, CHU Ambroise Pare, Mons, Belgium.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Holbrechts
authors.affiliation: Oncology Department, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Marc
authors.initials: M
authors.lastname: Van den Eynde
authors.affiliation: Gastroenterology Department, CHC ST Joseph, Liege, Belgium.
authors.forename: Ghislain
authors.initials: G
authors.lastname: Houbiers
authors.affiliation: Oncology Department, Jolimont Hospital, Haine-St-Paul, Belgium.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Filleul
authors.affiliation: Gastroenterology Medico-Surgical Department, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Van Laethem
authors.affiliation: Nuclear Medicine Department, Antwerp, University Hospital, Edegem, Belgium.
authors.forename: Sarah
authors.initials: S
authors.lastname: Ceyssens
authors.affiliation: Oncology Department, CHU Ambroise Pare, Mons, Belgium.
authors.forename: Anna-Maria
authors.initials: AM
authors.lastname: Barbuto
authors.affiliation: Nuclear Medicine Department, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Renaud
authors.initials: R
authors.lastname: Lhommel
authors.affiliation: Gastroenterology Department, CHC ST Joseph, Liege, Belgium.
authors.forename: Gauthier
authors.initials: G
authors.lastname: Demolin
authors.affiliation: Nuclear Medicine Department, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Camilo
authors.initials: C
authors.lastname: Garcia
authors.affiliation: Medical Oncology Department, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium; Oncology Department, Jolimont Hospital, Haine-St-Paul, Belgium; Gastroenterology Medico-Surgical Department, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium; Oncology Department, Antwerp University Hospital, Antwerp University, Edegem, Belgium; Nuclear Medicine Department, Antwerp, University Hospital, Edegem, Belgium; Oncology Department, CHU Ambroise Pare, Mons, Belgium; Oncology Department, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium; Nuclear Medicine Department, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium; Gastroenterology Department, CHC ST Joseph, Liege, Belgium; Nuclear Medicine Department, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Hazem
authors.initials: H
authors.lastname: El Mansy
authors.affiliation: Data centre, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Lieveke
authors.initials: L
authors.lastname: Ameye
authors.affiliation: Data centre, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Michel
authors.initials: M
authors.lastname: Moreau
authors.affiliation: Nuclear Medicine Department, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: Guiot
authors.affiliation: Data centre, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Marianne
authors.initials: M
authors.lastname: Paesmans
authors.affiliation: Medical Oncology Department, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Martine
authors.initials: M
authors.lastname: Piccart
authors.affiliation: Nuclear Medicine Department, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Flamen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D000069287:Capecitabine / Q000008:administration & dosage; D015179:Colorectal Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000401:mortality; D018572:Disease-Free Survival; D005260:Female; D019298:Glucose-6-Phosphate / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives; D010671:Phenylurea Compounds / Q000008:administration & dosage; D049268:Positron-Emission Tomography; D011446:Prospective Studies; D011859:Radiography; D000077157:Sorafenib; D015996:Survival Rate
chemical_list: D010671:Phenylurea Compounds; D009536:Niacinamide; C047515:2-fluoro-2-deoxyglucose-6-phosphate; D019298:Glucose-6-Phosphate; D000069287:Capecitabine; D000077157:Sorafenib