title: Efaproxiral red blood cell concentration predicts efficacy in patients with brain metastases.
abstract: Efaproxiral (Efaproxyn, RSR13), a synthetic allosteric modifier of haemoglobin (Hb), decreases Hb-oxygen (O(2)) binding affinity and enhances oxygenation of hypoxic tumours during radiation therapy. This analysis evaluated the Phase 3, Radiation Enhancing Allosteric Compound for Hypoxic Brain Metastases; RT-009 (REACH) study efficacy results in relation to efaproxiral exposure (efaproxiral red blood cell concentration (E-RBC) and number of doses). Recursive partitioning analysis Class I or II patients with brain metastases from solid tumours received standard whole-brain radiation therapy (3 Gy/fraction x 10 days), plus supplemental O(2) (4 l/min), either with efaproxiral (75 or 100 mg/kg daily) or without (control). Efaproxiral red blood cell concentrations were linearly extrapolated to all efaproxiral doses received. Three patient populations were analysed: (1) all eligible, (2) non-small-cell lung cancer (NSCLC) as primary cancer, and (3) breast cancer primary. Efficacy endpoints were survival and response rate. Brain metastases patients achieving sufficient E-RBC (> or =483 microg/ml) and receiving at least seven of 10 efaproxiral doses were most likely to experience survival and response benefits. Patients with breast cancer primary tumours generally achieved the target efaproxiral exposure and therefore gained greater benefit from efaproxiral treatment than NSCLC patients. This analysis defined the efaproxiral concentration-dependence in survival and response rate improvement, and provided a clearer understanding of efaproxiral dosing requirements.
authors.affiliation: Department of Radiation Oncology, The University of Arizona Health Sciences Center, Tucson, 85724, USA. bstea@azcc.arizona.edu
authors.forename: B
authors.initials: B
authors.lastname: Stea
authors.forename: E
authors.initials: E
authors.lastname: Shaw
authors.forename: T
authors.initials: T
authors.lastname: Pintér
authors.forename: J
authors.initials: J
authors.lastname: Hackman
authors.forename: M
authors.initials: M
authors.lastname: Craig
authors.forename: J
authors.initials: J
authors.lastname: May
authors.forename: R P
authors.initials: RP
authors.lastname: Steffen
authors.forename: J H
authors.initials: JH
authors.lastname: Suh
mesh_terms: D000814:Aniline Compounds / Q000008:administration & dosage*; D000986:Antisickling Agents / Q000008:administration & dosage*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy / Q000556:secondary; D001943:Breast Neoplasms / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000737:chemistry*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011422:Propionates / Q000008:administration & dosage*; D016019:Survival Analysis
chemical_list: D000814:Aniline Compounds; D000986:Antisickling Agents; D011422:Propionates; C067396:efaproxiral