Effects of sorafenib on intra-tumoral interstitial fluid pressure and circulating biomarkers in patients with refractory sarcomas (NCI protocol 6948)

PLoS One. 2012;7(2):e26331. doi: 10.1371/journal.pone.0026331. Epub 2012 Feb 7.


Purpose: Sorafenib is a multi-targeted tyrosine kinase inhibitor with therapeutic efficacy in several malignancies. Sorafenib may exert its anti-neoplastic effect in part by altering vascular permeability and reducing intra-tumoral interstitial hypertension. As correlative science with a phase II study in patients with advanced soft-tissue sarcomas (STS), we evaluated the impact of this agent on intra-tumor interstitial fluid pressure (IFP), serum circulating biomarkers, and vascular density.

Patients and methods: Patients with advanced STS with measurable disease and at least one superficial lesion amenable to biopsy received sorafenib 400 mg twice daily. Intratumoral IFP and plasma and circulating cell biomarkers were measured before and after 1-2 months of sorafenib administration. Results were analyzed in the context of the primary clinical endpoint of time-to-progression (TTP).

Results: In 15 patients accrued, the median TTP was 45 days (range 14-228). Intra-tumoral IFP measurements obtained in 6 patients at baseline showed a direct correlation with tumor size. Two patients with stable disease at two months had post-sorafenib IFP evaluations and demonstrated a decline in IFP and vascular density. Sorafenib significantly increased plasma VEGF, PlGF, and SDF1α and decreased sVEGFR-2 levels. Increased plasma SDF1α and decreased sVEGFR-2 levels on day 28 correlated with disease progression.

Conclusions: Pretreatment intra-tumoral IFP correlated with tumor size and decreased in two evaluable patients with SD on sorafenib. Sorafenib also induced changes in circulating biomarkers consistent with expected VEGF pathway blockade, despite the lack of more striking clinical activity in this small series.

Trial registration: ClinicalTrials.gov NCT00330421.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Angiogenic Proteins / analysis
  • Angiogenic Proteins / blood
  • Antineoplastic Agents
  • Benzenesulfonates / administration & dosage
  • Benzenesulfonates / pharmacology*
  • Benzenesulfonates / therapeutic use
  • Biomarkers, Tumor / blood*
  • Capillary Permeability / drug effects
  • Extracellular Fluid / drug effects*
  • Female
  • Humans
  • Male
  • Middle Aged
  • Niacinamide / analogs & derivatives
  • Phenylurea Compounds
  • Pressure
  • Protein Kinase Inhibitors
  • Pyridines / administration & dosage
  • Pyridines / pharmacology*
  • Pyridines / therapeutic use
  • Salvage Therapy
  • Sarcoma / drug therapy*
  • Sorafenib
  • Vascular Endothelial Growth Factors / drug effects


  • Angiogenic Proteins
  • Antineoplastic Agents
  • Benzenesulfonates
  • Biomarkers, Tumor
  • Phenylurea Compounds
  • Protein Kinase Inhibitors
  • Pyridines
  • Vascular Endothelial Growth Factors
  • Niacinamide
  • Sorafenib

Associated data

  • ClinicalTrials.gov/NCT00330421