title: Decreased tumor blood flow as measured by positron emission tomography in cancer patients treated with interleukin-1 and carboplatin on a phase I trial.
abstract: BACKGROUND
  Positron emission tomography (PET) scanning can be used to measure blood flow. When interleukin-1alpha (IL-1) is given in a murine model, it induces acute hemorrhagic necrosis, tumor vascular injury and decreased tumor blood flow, and when given prior to carboplatin, there is enhanced antitumor activity compared to either agent alone.
  
  
  METHODS
  In a phase I trial of IL-1 and carboplatin, eligible patients with metastatic disease to the lung had PET scanning performed with (15)O water to assess tumor blood flow before and after IL-1 administration. Doses of IL-1 were 0.03, 0.06, 0.10, 0.15, 0.20 and 0.30 micro g/kg given i.v. over 2 h. At 4 h after IL-1 initiation, carboplatin was administered as a 30-min i.v. infusion at a dose of 400 mg/m(2). Treatment was repeated every 28 days. Other measured parameters included granulocyte kinetics, integrin expression on circulating WBC, and carboplatin pharmacokinetics. Of 16 patients, 11 (8 evaluable) underwent PET scanning before and at 2, 4 and 24 h after IL-1 initiation.
  
  
  RESULTS
  Mean measured pretreatment tumor blood flow was 1.82 ml/min per g. At 2, 4 and 24 h it was 1.35, 1.67 and 1.62 ml/min per g respectively. Tumor blood flow was significantly decreased ( P<0.008) at 2 h after IL-1 initiation. In four patients, liver blood flow was measured at the same time-points as tumor blood flow. Liver blood flow was discordant with the tumor blood flow measures, showing no statistically significant change. IL-1 also caused a decreased WBC at 2 h after initiation ( n=14, P=0.025). In addition, polymorphonuclear leukocyte (PMN) and monocyte surface expression of CD11b at 2 h was increased when measured by mean fluorescence intensity flow cytometry (PMN P=0.0269, monocytes P=0.0420). No consistent effect of IL-1 on either carboplatin AUC or platelet nadir was demonstrated.
  
  
  CONCLUSIONS
  We conclude that IL-1 has measurable effects on tumor blood flow and causes a significant decrease in blood flow as measured by PET scanning with (15)O water at 2 h after initiation. This decrease is temporally associated with a significant leukopenia and an increased expression of the adhesion integrin CD11b on the circulating cell surface (PMN and monocytes). These results suggest that IL-1 causes decreased tumor blood flow in vivo in human cancer patients, an effect that was temporally related to cytokine-induced peripheral blood cellular changes. Furthermore, our findings suggest that PET scanning may be useful to assess the effect of a systemic antineoplastic agent on tumor blood flow in cancer patients.
authors.affiliation: University of Pittsburgh, Pennsylvania 15260, USA. tlogan@iupui.edu
authors.forename: Theodore F
authors.initials: TF
authors.lastname: Logan
authors.forename: Fayega
authors.initials: F
authors.lastname: Jadali
authors.forename: Merrill J
authors.initials: MJ
authors.lastname: Egorin
authors.forename: Mark
authors.initials: M
authors.lastname: Mintun
authors.forename: Donald
authors.initials: D
authors.lastname: Sashin
authors.forename: William E
authors.initials: WE
authors.lastname: Gooding
authors.forename: Yong
authors.initials: Y
authors.lastname: Choi
authors.forename: Harry
authors.initials: H
authors.lastname: Bishop
authors.forename: Donald L
authors.initials: DL
authors.lastname: Trump
authors.forename: Diane
authors.initials: D
authors.lastname: Gardner
authors.forename: John
authors.initials: J
authors.lastname: Kirkwood
authors.forename: Daniel
authors.initials: D
authors.lastname: Vlock
authors.forename: Candace
authors.initials: C
authors.lastname: Johnson
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D019540:Area Under Curve; D001772:Blood Cell Count; D001783:Blood Flow Velocity; D039481:CD11b Antigen / Q000378:metabolism; D016190:Carboplatin / Q000627:therapeutic use*; D002448:Cell Adhesion; D015536:Down-Regulation; D004359:Drug Therapy, Combination; D005260:Female; D006098:Granulocytes / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000098:blood supply* / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000000981:diagnostic imaging* / Q000378:metabolism; D010104:Oxygen Radioisotopes; D014055:Tomography, Emission-Computed
chemical_list: D000970:Antineoplastic Agents; D039481:CD11b Antigen; D007375:Interleukin-1; D010104:Oxygen Radioisotopes; D016190:Carboplatin