title: Monitoring response to antiangiogenic treatment and predicting outcomes in advanced hepatocellular carcinoma using image biomarkers, CT perfusion, tumor density, and tumor size (RECIST).
abstract: OBJECTIVE
  Our aim was to investigate the hypothesis that the CT perfusion (CTP) is a more sensitive image biomarker when compared with tumor burden (Response Evaluation Criteria in Solid Tumors [RECIST]) and tumor density (HU) for monitoring treatment changes and for predicting long-term outcome in advanced hepatocellular carcinoma (HCC) treated with a combination of antiangiogenic treatment and chemotherapy.
  
  
  METHODS
  In this phase II clinical trial, 33 patients with advanced HCC were enrolled and 23 were included in the current study. A diagnostic dual-phase contrast-enhanced CT and perfusion CT was performed at baseline and days 10 to 12 after initiation of antiangiogenic treatment (Bevacizumab). The patients subsequently received bevacizumab in combination with gemcitabine and oxaliplatin (GEMOX-B) and contrast-enhanced CT was performed at the end of treatment (after completing 3 cycles of GEMOX-B chemotherapy) and after every 8 week until there was evidence of disease progression or intolerable toxicity. The CTP protocol included a targeted dynamic cine acquisition for 25 to 30 seconds after 50 to 70 mL of iodinated contrast media injection at 5 to 7 mL/s. The CTP parameters were compared with tumor size (according to Response Evaluation Criteria in Solid Tumors, RECIST 1.1) and density measurements (HU) before and after treatment and correlated with patient's outcome in groups with and without tumor thrombus. A one-sided P value was calculated and the Bonferroni correction was used to address the issue of multiple comparisons.
  
  
  RESULTS
  On days 10 to 12 after initiation of bevacizumab, significant decrease in CTP parameters was noted (P < 0.005). There was a mild reduction in mean tumor density (P = 0.016) without any significant change in mean tumor size. Tumors with higher baseline mean transit time values on CTP correlated with favorable clinical outcome (partial response and stable disease) and had better 6 months progression-free survival (P = 0.002 and P = 0.005, respectively). The baseline transfer constant (Ktrans) of responders (1425.19 ± 609.47 mL/1000 mL/min) was significantly higher than that of nonresponders (935.96 ± 189.47 mL/1000 mL/min). The tumor thrombus in the portal vein demonstrated baseline perfusion values and post-treatment change values similar to the HCC.
  
  
  CONCLUSIONS
  In advanced HCC, CTP is a more sensitive image biomarker for monitoring early antiangiogenic treatment effects as well as in predicting outcome at the end of treatment and progression-free survival as compared with RECIST and tumor density.
authors.affiliation: Division of Abdominal Imaging and Intervention, Harvard Medical School and Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Jiang
authors.forename: Avinash
authors.initials: A
authors.lastname: Kambadakone
authors.forename: Naveen M
authors.initials: NM
authors.lastname: Kulkarni
authors.forename: Andrew X
authors.initials: AX
authors.lastname: Zhu
authors.forename: Dushyant V
authors.initials: DV
authors.lastname: Sahani
mesh_terms: D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D014408:Biomarkers, Tumor / Q000032:analysis; D006528:Carcinoma, Hepatocellular / Q000000981:diagnostic imaging* / Q000188:drug therapy*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D008113:Liver Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D055420:Perfusion Imaging / Q000379:methods*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014057:Tomography, X-Ray Computed / Q000379:methods*; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; D009944:Organoplatinum Compounds; D003841:Deoxycytidine