title: Dynamic microbubble contrast-enhanced US to measure tumor response to targeted therapy: a proposed clinical protocol with results from renal cell carcinoma patients receiving antiangiogenic therapy.
abstract: OBJECTIVE
  To develop and implement an evidence-based protocol for characterizing vascular response of renal cell carcinoma (RCC) to targeted therapy by using dynamic contrast material-enhanced (DCE) ultrasonography (US).
  
  
  METHODS
  The study was approved by the institutional research ethics board; written informed consent was obtained from all patients. Seventeen patients (four women; median age, 58 years; range, 42-72 years; 13 men, median age, 62 years; range, 45-81 years) with metastatic RCC were examined by using DCE US before and after 2 weeks of treatment with sunitinib (May 2007 to October 2009). Two contrast agent techniques--bolus injection and disruption-replenishment infusion of microbubbles--were compared. Changes in tumor blood velocity and fractional blood volume were measured with both methods, together with reproducibility and effect of compensation for respiratory motion. Tumor changes were assessed with computed tomography, by using the best response with the Response Evaluation Criteria in Solid Tumors (RECIST) and progression-free survival (PFS). Follow-up RECIST measurements were performed at 6-week intervals until progressive disease was detected.
  
  
  RESULTS
  In response to treatment, median tumor fractional blood volume measured with the disruption-replenishment infusion method decreased by 73.2% (interquartile range, 46%-87%) (P < .002), with repeated-measure reproducibility of 9%-15%. Significant decreases were also seen with the bolus method, but with poor correlation of changes in bolus peak (r = 0.46, P = .066) and area under the curve (r = 0.47, P = .058), compared with infusion measurements. Changes in DCE US parameters over 2 weeks did not correlate with PFS and could not be used to predict long-term assessment of best response by using RECIST. Follow-up times ranged 28-501 days; the median was 164 days.
  
  
  CONCLUSIONS
  DCE US provides reproducible and sensitive assessment of vascular changes in response to antiangiogenic therapy. The disruption-replenishment infusion protocol is a flexible method suitable for many tumor types, but further studies are needed to assess whether this protocol may be predictive of patient outcome.
authors.affiliation: Imaging Research, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Ave, Room S6-39, Toronto, ON, Canada M4N 3M5. williams@sri.utoronto.ca
authors.forename: Ross
authors.initials: R
authors.lastname: Williams
authors.forename: John M
authors.initials: JM
authors.lastname: Hudson
authors.forename: Brendan A
authors.initials: BA
authors.lastname: Lloyd
authors.forename: Ahthavan R
authors.initials: AR
authors.lastname: Sureshkumar
authors.forename: Gordon
authors.initials: G
authors.lastname: Lueck
authors.forename: Laurent
authors.initials: L
authors.lastname: Milot
authors.forename: Mostafa
authors.initials: M
authors.lastname: Atri
authors.forename: Georg A
authors.initials: GA
authors.lastname: Bjarnason
authors.forename: Peter N
authors.initials: PN
authors.lastname: Burns
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D019540:Area Under Curve; D002292:Carcinoma, Renal Cell / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000473:pathology; D003287:Contrast Media; D019317:Evidence-Based Medicine; D005260:Female; D005466:Fluorocarbons; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D045423:Microbubbles; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011758:Pyrroles / Q000627:therapeutic use*; D015203:Reproducibility of Results; D018709:Statistics, Nonparametric; D000077210:Sunitinib; D016019:Survival Analysis; D014057:Tomography, X-Ray Computed; D014463:Ultrasonography
chemical_list: D020533:Angiogenesis Inhibitors; D003287:Contrast Media; D005466:Fluorocarbons; D007211:Indoles; D011758:Pyrroles; D000077210:Sunitinib; C042852:perflutren