title: Early increase in circulating carbonic anhydrase IX during neoadjuvant treatment predicts favourable outcome in locally advanced rectal cancer.
abstract: BACKGROUND
  Locally advanced rectal cancer (LARC) comprises heterogeneous tumours with predominant hypoxic components. The hypoxia-inducible metabolic shift causes microenvironmental acidification generated by carbonic anhydrase IX (CAIX) and facilitates metastatic progression, the dominant cause of failure in LARC.
  
  
  METHODS
  Using a commercially available immunoassay, circulating CAIX was assessed in prospectively archived serial serum samples collected during combined-modality neoadjuvant treatment of LARC patients and correlated to histologic tumour response and progression-free survival (PFS).
  
  
  RESULTS
  Patients who from their individual baseline level displayed serum CAIX increase above a threshold of 224 pg/ml (with 96 % specificity and 39 % sensitivity) after completion of short-course neoadjuvant chemotherapy (NACT) prior to long-course chemoradiotherapy and definitive surgery had significantly better 5-year PFS (94 %) than patients with below-threshold post-NACT versus baseline alteration (PFS rate of 56 %; p < 0.01). This particular CAIX parameter, ΔNACT, was significantly correlated with histologic ypT0-2 and ypN0 outcome (p < 0.01) and remained an independent PFS predictor in multivariate analysis wherein it was entered as continuous variable (p = 0.04).
  
  
  CONCLUSIONS
  Our results indicate that low ΔNACT, i.e., a weak increase in serum CAIX level following initial neoadjuvant treatment (in this case two cycles of the Nordic FLOX regimen), might be used as risk-adapted stratification to postoperative therapy or other modes of intensification of the combined-modality protocol in LARC.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00278694.
authors.affiliation: Institute of Clinical Medicine, University of Oslo, P.O. Box 1171, Blindern, 0318, Oslo, Norway. helga.hektoen@medisin.uio.no.|Department of Oncology, Akershus University Hospital, P.O. Box 1000, 1478, Lørenskog, Norway. helga.hektoen@medisin.uio.no.|Department of Tumour Biology, Oslo University Hospital - Norwegian Radium Hospital, P.O.Box 4950, Nydalen, 0424, Oslo, Norway. helga.hektoen@medisin.uio.no.
authors.forename: Helga Helseth
authors.initials: HH
authors.lastname: Hektoen
authors.affiliation: Institute of Clinical Medicine, University of Oslo, P.O. Box 1171, Blindern, 0318, Oslo, Norway. Kjersti.Flatmark@rr-research.no.|Department of Tumour Biology, Oslo University Hospital - Norwegian Radium Hospital, P.O.Box 4950, Nydalen, 0424, Oslo, Norway. Kjersti.Flatmark@rr-research.no.|Department of Gastroenterological Surgery, Oslo University Hospital - Norwegian Radium Hospital, P.O.Box 4950, Nydalen, 0424, Oslo, Norway. Kjersti.Flatmark@rr-research.no.
authors.forename: Kjersti
authors.initials: K
authors.lastname: Flatmark
authors.affiliation: Department of Tumour Biology, Oslo University Hospital - Norwegian Radium Hospital, P.O.Box 4950, Nydalen, 0424, Oslo, Norway. Yvonne.Andersson@rr-research.no.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Andersson
authors.affiliation: Department of Oncology, Oslo University Hospital - Norwegian Radium Hospital, P.O.Box 4950, Nydalen, 0424, Oslo, Norway. svedue@ous-hf.no.
authors.forename: Svein
authors.initials: S
authors.lastname: Dueland
authors.affiliation: Department of Oncology, Akershus University Hospital, P.O. Box 1000, 1478, Lørenskog, Norway. k.r.redalen@medisin.uio.no.
authors.forename: Kathrine Røe
authors.initials: KR
authors.lastname: Redalen
authors.affiliation: Institute of Clinical Medicine, University of Oslo, P.O. Box 1171, Blindern, 0318, Oslo, Norway. a.h.ree@medisin.uio.no.|Department of Oncology, Akershus University Hospital, P.O. Box 1000, 1478, Lørenskog, Norway. a.h.ree@medisin.uio.no.
authors.forename: Anne Hansen
authors.initials: AH
authors.lastname: Ree
mesh_terms: D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000097:blood*; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000097:blood*; D059186:Chemoradiotherapy, Adjuvant / Q000379:methods; D017024:Chemotherapy, Adjuvant / Q000379:methods; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000379:methods*; D011446:Prospective Studies; D012004:Rectal Neoplasms / Q000097:blood / Q000201:enzymology* / Q000628:therapy*; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000951:Antigens, Neoplasm; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases