title: A phase I trial of human corticotropin-releasing factor (hCRF) in patients with peritumoral brain edema.
abstract: BACKGROUND
  Human corticotropin-releasing factor (hCRF) is an endogenous peptide responsible for the secretion and synthesis of corticosteroids. In animal models of peritumoral brain edema, hCRF has significant anti-edematous action. This effect, which appears to be independent of the release of adrenal steroids, appears mediated by a direct effect on endothelial cells. We conducted a feasibility and phase I study with hCRF given by continuous infusion to patients with brain metastasis.
  
  
  METHODS
  Peritumoral brain edema documented by MRI and the use of either no steroids or stable steroid doses for more than a week were required. MRIs were repeated at completion of infusion and estimations by dual echo-image sequence (Proton density and T2-weighted images) of the amount of peritumoral edema were performed. The study was performed in two stages. In the feasibility part, patients were randomized to receive either 0.66 or 1 microgram/kg/h of hCRF or placebo over 24 hours. The second part was a dose finding study of hCRF over 72 hours at escalating doses.
  
  
  RESULTS
  Seventeen patients were enrolled; only one was receiving steroids (stable doses) at study entrance; dose-limiting toxicity (hypotension) was observed at 4 micrograms/kg/h x 72 hours in two out of four patients, while zero of five patients treated at 2 micrograms/kg/h developed dose-limiting toxicities. Flushing and hot flashes were also observed. Improvement of neurological symptoms and/or exam were seen in 10 patients. Only small changes were detected by MRI. Improvement in symptoms did not correlate with changes in cortisol levels, and changes in cortisol levels were not correlated with changes in peritumoral edema.
  
  
  CONCLUSIONS
  hCRF is well tolerated in doses up to 2 micrograms/kg/h by continuous infusion x 72 hours. Hypotension limits administration of higher doses. The observation of clinical benefit in the absence of corticosteroids suggests hCRF may be an alternative to steroids for the treatment of patients with peritumoral brain edema. Further exploration of this agent in efficacy studies is warranted.
authors.affiliation: Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Villalona-Calero
authors.forename: J
authors.initials: J
authors.lastname: Eckardt
authors.forename: H
authors.initials: H
authors.lastname: Burris
authors.forename: M
authors.initials: M
authors.lastname: Kraynak
authors.forename: S
authors.initials: S
authors.lastname: Fields-Jones
authors.forename: C
authors.initials: C
authors.lastname: Bazan
authors.forename: J
authors.initials: J
authors.lastname: Lancaster
authors.forename: T
authors.initials: T
authors.lastname: Hander
authors.forename: R
authors.initials: R
authors.lastname: Goldblum
authors.forename: L
authors.initials: L
authors.lastname: Hammond
authors.forename: A
authors.initials: A
authors.lastname: Bari
authors.forename: R
authors.initials: R
authors.lastname: Drengler
authors.forename: M
authors.initials: M
authors.lastname: Rothenberg
authors.forename: G
authors.initials: G
authors.lastname: Hadovsky
authors.forename: D D
authors.initials: DD
authors.lastname: Von Hoff
mesh_terms: D000311:Adrenal Glands / Q000502:physiology; D000315:Adrenalectomy; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001929:Brain Edema / Q000175:diagnosis / Q000188:drug therapy* / Q000209:etiology; D001932:Brain Neoplasms / Q000150:complications* / Q000473:pathology; D003346:Corticotropin-Releasing Hormone / Q000009:adverse effects / Q000627:therapeutic use*; D003907:Dexamethasone / Q000627:therapeutic use*; D004311:Double-Blind Method; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D015996:Survival Rate
chemical_list: D018931:Antineoplastic Agents, Hormonal; D003907:Dexamethasone; D003346:Corticotropin-Releasing Hormone; D006854:Hydrocortisone