title: Elevated tumor lactate concentrations predict for an increased risk of metastases in head-and-neck cancer.
abstract: OBJECTIVE
  Hypoxia shifts the balance of cellular energy production toward glycolysis with lactate generation as a by-product. Quantitative bioluminescence imaging allows for the quantitation of lactate concentrations in individual tumors. We assessed the relationship between pretreatment tumor lactate concentrations and subsequent development of metastatic disease in patients with newly diagnosed head-and-neck cancer.
  
  
  METHODS
  At the time of biopsy of the primary site, a separate specimen was taken and flash-frozen for subsequent quantitation of lactate concentration using a luciferase bioluminescence technique. The two-dimensional spatial distribution of the bioluminescence intensity within the tissue section was registered directly using a microscope and an imaging photon counting system. Photon intensity was converted to distributions of volume-related tissue concentrations (micromol per gram wet weight). Treatment consisted of either surgery and postoperative radiotherapy or primary radiotherapy, based on presenting disease stage and institutional treatment policies. The subsequent development of metastatic disease constituted the primary clinical endpoint.
  
  
  RESULTS
  Biopsies obtained from 40 patients were evaluable in 34. The larynx was the most frequent primary site (n = 25). Other sites included oropharynx (n = 5), hypopharynx (n = 3), and oral cavity (n = 1). Most patients (74%) presented with an advanced stage T3 or T4 primary tumor. Nodal involvement was present in 19 (54%) patients. The median tumor lactate concentration was 7.1 micromol/g. Tumors were classified as having either low or high lactate concentrations according to whether these values were below or above the median. The median follow-up time for surviving patients is 27 months. Two-year actuarial survival was 90% for patients with low-lactate-concentration tumor vs. 35% for patients with high-lactate-concentration primaries (<0.0001). Two-year metastasis-free survival was adversely influenced by high tumor lactate concentrations (90% vs. 25%, p < 0.0001). The median lactate concentration for tumors that subsequently metastasized was 12.9 micromol/g vs. 4.8 micromol/g for patients who remained continuously free of disease (p < 0.005). Lactate concentration was not correlated with presenting T stage or N stage.
  
  
  CONCLUSIONS
  Elevated tumor lactate concentrations are associated with the subsequent development of nodal or distant metastases in head-and-neck cancer patients. This more aggressive malignant phenotype is probably associated with hypoxia-mediated radioresistance and the upregulation of metastasis-associated genes.
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA. brizel@radonc.duke.edu
authors.forename: D M
authors.initials: DM
authors.lastname: Brizel
authors.forename: T
authors.initials: T
authors.lastname: Schroeder
authors.forename: R L
authors.initials: RL
authors.lastname: Scher
authors.forename: S
authors.initials: S
authors.lastname: Walenta
authors.forename: R W
authors.initials: RW
authors.lastname: Clough
authors.forename: M W
authors.initials: MW
authors.lastname: Dewhirst
authors.forename: W
authors.initials: W
authors.lastname: Mueller-Klieser
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis*; D002294:Carcinoma, Squamous Cell / Q000737:chemistry* / Q000473:pathology / Q000532:radiotherapy; D015687:Cell Hypoxia; D005500:Follow-Up Studies; D006258:Head and Neck Neoplasms / Q000737:chemistry* / Q000473:pathology / Q000532:radiotherapy; D006801:Humans; D019344:Lactic Acid / Q000032:analysis*; D007822:Laryngeal Neoplasms / Q000532:radiotherapy; D009062:Mouth Neoplasms / Q000532:radiotherapy; D010610:Pharyngeal Neoplasms / Q000532:radiotherapy
chemical_list: D014408:Biomarkers, Tumor; D019344:Lactic Acid