title: Pharmacodynamic study of axitinib in patients with advanced malignancies assessed with (18)F-3'deoxy-3'fluoro-L-thymidine positron emission tomography/computed tomography.
abstract: OBJECTIVE
  Rapid disease progression associated with increased tumor proliferation has been observed during withdrawal of anti-angiogenic therapy. We characterize the dynamics of withdrawal flare for axitinib.
  
  
  METHODS
  Thirty patients with metastatic solid malignancies received axitinib for 2 weeks, followed by a 1-week drug holiday. Twenty patients suitable for PET imaging received scans with (18)F-3'deoxy-3'fluoro-L-thymidine (FLT), a marker of proliferation. Plasma VEGF and axitinib pharmacokinetic levels were also assessed at specified time points.
  
  
  RESULTS
  During axitinib withdrawal, significant increases in both SUVmax (+22 %; p = 0.006) and SUVmean (+20 %; p = 0.001) were observed. Significant increases relative to peak axitinib concentration were observed at day 2 withdrawal for SUVmax and SUVmean, with no further significant increase from day 2 to day 7 of withdrawal. No significant change in SUVmax or SUVmean was observed during the treatment period, relative to baseline. VEGF concentration significantly increased when on drug (p < 0.001) and decreased back to a level indistinguishable from baseline by day 7 of drug washout (p = 0.448). No correlation between change in VEGF and change in imaging metrics was observed.
  
  
  CONCLUSIONS
  A significant increase in tumor proliferation was observed during withdrawal of axitinib therapy, and this flare occurred within 2 days of axitinib withdrawal. An exploratory analysis indicated that this flare may be associated with poor clinical outcome.
authors.affiliation: Department of Medicine, University of Wisconsin Carbone Cancer Center, 7105 Wisconsin Institute Medical Research, 1111 Highland Ave, Madison, WI, 53705, USA, jybruce@medicine.wisc.edu.
authors.forename: Justine Yang
authors.initials: JY
authors.lastname: Bruce
authors.forename: Peter Colin
authors.initials: PC
authors.lastname: Scully
authors.forename: Lakeesha L
authors.initials: LL
authors.lastname: Carmichael
authors.forename: Jens C
authors.initials: JC
authors.lastname: Eickhoff
authors.forename: Scott B
authors.initials: SB
authors.lastname: Perlman
authors.forename: Jill Marie
authors.initials: JM
authors.lastname: Kolesar
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Heideman
authors.forename: Robert
authors.initials: R
authors.lastname: Jeraj
authors.forename: Glenn
authors.initials: G
authors.lastname: Liu
mesh_terms: D000328:Adult; D000368:Aged; D000077784:Axitinib; D015224:Dideoxynucleosides; D018450:Disease Progression; D005260:Female; D005462:Fluorine Radioisotopes; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D007191:Indazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D064847:Multimodal Imaging / Q000379:methods; D009369:Neoplasms / Q000097:blood / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism; D049268:Positron-Emission Tomography / Q000379:methods; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals; D013375:Substance Withdrawal Syndrome / Q000097:blood / Q000000981:diagnostic imaging / Q000209:etiology / Q000378:metabolism; D014057:Tomography, X-Ray Computed / Q000379:methods; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
chemical_list: D015224:Dideoxynucleosides; D005462:Fluorine Radioisotopes; D007093:Imidazoles; D007191:Indazoles; D047428:Protein Kinase Inhibitors; D019275:Radiopharmaceuticals; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000077784:Axitinib; C002854:alovudine